Monoamine transmitter reuptake inhibitor compound as well as preparation method and application thereof

Abstract

The invention provides a monoamine transmitter reuptake inhibitor as well as a preparation method and a pharmaceutical composition thereof. The invention also relates to application of the compound or the pharmaceutical composition in preparation of drugs for preventing or treating dopamine DA, noradrenaline NE, 5-hydroxytryptamine 5-HT and / or sigma-1 receptor mediated related diseases.

Description

[0001] This application claims priority to Chinese Application No. 202410542159.X, filed on April 30, 2024; Chinese Application No. 202411138885.1, filed on August 19, 2024; and Chinese Application No. 202510117370.1, filed on January 24, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a class of monoamine neurotransmitter reuptake inhibitor compounds, a method for preparing said compounds, and the use of said compounds in the treatment of central nervous system (CNS) diseases or disorders. Background Technology

[0003] The pathogenesis of neurological diseases is complex, involving multiple pathological processes such as neurotransmitter imbalance, neuronal damage, and inflammatory responses. Monoamine neurotransmitter transporter inhibitors and Sigma-1 receptor modulators, as two important drug targets, have demonstrated unique clinical value in the treatment of diseases such as depression, Alzheimer's disease (AD), and schizophrenia.

[0004] Monoamine neurotransmitter transporter inhibitors (such as norepinephrine transporter NET, serotonin transporter SERT, and dopamine transporter DAT) inhibit neurotransmitter reuptake by blocking the function of monoamine neurotransmitter transporters in the synaptic cleft, thereby increasing neurotransmitter concentration in the synaptic cleft and maintaining neurotransmitter dynamic balance, thus treating a variety of neurological diseases.

[0005] Monoamine neurotransmitter transporter inhibitors (MTAs) are the core targets of antidepressants, improving depressive symptoms by regulating the synaptic concentrations of neurotransmitters such as norepinephrine (NE), serotonin (5-HT), and dopamine (DA). Selective serotonin reuptake inhibitors (SSRIs, such as fluoxetine and escitalopram) and dual serotonin / NE reuptake inhibitors (SNRIs, such as venlafaxine and duloxetine) are first-line drugs for depression. Selective NE reuptake inhibitors (NRIs, such as reboxetine) and DA / NE reuptake inhibitors (NDRIs, such as bupropion) have also been approved for the treatment of depression. Triple reuptake inhibitors, as novel multi-target antidepressants, offer higher specificity, faster action, and fewer adverse reactions, compensating for the shortcomings of traditional antidepressants in clinical application and representing a key research direction for novel antidepressants. Furthermore, the functions of DAT and NET are also associated with attention deficit hyperactivity disorder (ADHD), expanding the clinical application scope of MATs. Methylphenidate and atomoxetine exert their therapeutic effects by inhibiting DAT and NET, respectively, and enhancing dopamine and / or norepinephrine signaling, and have been widely used in the treatment of ADHD. Centanafadine, a triple reuptake inhibitor of DA, NE, and 5-HT, is being developed for the treatment of ADHD in children, adolescents, and adults. In phase III clinical trials for the treatment of ADHD in adults and adolescents and children with ADHD, it met its primary endpoint, significantly improving patient symptoms and demonstrating good tolerability.

[0006] The Sigma-1 receptor (σ-1R or S1R) is located on the mitochondrial-associated membrane (MAM) and functions as both a molecular chaperone and a receptor-like agent. It protects neurons through mechanisms such as regulating calcium homeostasis, mitochondrial function, and anti-oxidative stress, and participates in the regulation of neurotransmitter release (e.g., glutamate, dopamine). Sigma-1 receptor agonists improve depressive-like behaviors by enhancing the function of the 5-HT and NE systems. For example, fluvoxamine, possessing both SSRI and Sigma-1 agonist activity, may alleviate depressive symptoms through a dual mechanism. Sigma-1 receptors also participate in the regulation of reward circuits in drug addiction such as cocaine, and their antagonists may be potential drugs for withdrawal treatment. Blarcamesine (ANAVEX2-73), an oral small-molecule agonist targeting Sigma-1, effectively improves intracellular mitochondrial activation levels and neuroinflammation. Preclinical studies have demonstrated its beneficial effects on mitochondrial dysfunction and neuroinflammation, and it has been tested in multiple clinical trials to explore its potential in treating Alzheimer's disease, Parkinson's disease, and Rett syndrome.

[0007] The functions of Sigma-1 receptor modulators and monoamine neurotransmitter inhibitors can also be coordinated, providing new insights into complex diseases such as AD combined with depression. Summary of the Invention

[0008] This invention provides a series of compounds with norepinephrine-dopamine-serotonin reuptake inhibition and / or Sigma-1 receptor regulatory activity. By simultaneously inhibiting the reuptake of three monoamine neurotransmitters (norepinephrine NE, dopamine DA, and serotonin 5-HT) and / or regulating Sigma-1 receptor affinity activity, these compounds improve central neurotransmitter conduction and can improve neurological symptoms and treat neurological diseases.

[0009] In one aspect of the invention, compounds of formula (II), pharmaceutically acceptable salts thereof, stereoisomers, or deuterated derivatives are provided:

[0010]

[0011] in,

[0012] R1 is selected from:

[0013] R 1a and R 1b Each is independently selected from: H, or C 1-6 alkyl;

[0014] m is selected from 0, 1, 2, or 3;

[0015] n is selected from 0, 1, 2, or 3;

[0016] R 2a Selected from: H, or OH;

[0017] R 2b Selected from: H, or OH;

[0018] Or R 2a and R 2b Together with the carbon atoms they are attached to, they form rings.

[0019] X 2a and X 2c One of them is selected from: NR4, N, O, or S, and the other is selected from: C(R4)2, CR4, NR4, N, O, or S.

[0020] X 2b Selected from CR4 or C(R4)2;

[0021] Each occurrence is independently selected from either a single bond or a double bond;

[0022] The condition is when X 2a and / or X 2c When it is O or S, it is related to X. 2a and / or X 2c Connected Selected from single bonds;

[0023] Each R4 is independently selected from: H, halogen, or C. 1-6 alkyl;

[0024] Y2 is selected from: CR 2c 、 or N;

[0025] R 2c Selected from: H, halogen, or C 1-6 alkyl;

[0026] R 2d Selected from: H, halogen, or C 1-6 alkyl;

[0027] R3 is selected from:

[0028] R 3a Selected from: H, halogen, OH, or oxo group (=O);

[0029] R 3b Selected from: C 3-10 cycloalkyl, C 6-10 Aryl, or 5-6 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl or 5-6 heteroaryl group is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0030] R 3c Selected from: H, or OH;

[0031] X 3a X 3b X 3c X 3d X 3e Each is independently selected from C(R7)2, NR7, or O;

[0032] Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being C(R7)2;

[0033] R 5a and R 5b Each is independently selected from H, halogen, OH, or R. 5a R 5b Together with the carbon atoms they are attached to, they form a cyclopropyl group;

[0034] R6 is independently selected from: H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0035] R7 is independently selected from: H, halogen, C 1-6 Alkyl, or C 1-6 Alkyl group.

[0036] In some embodiments of the present invention, R1 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, isopropyl; m is selected from 0, 1, 2, or 3; other variables are as defined in this invention.

[0037] In some embodiments of the present invention, R1 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 1a Selected from: H, methyl, ethyl, n-propyl, isopropyl; m is selected from 0, 1, 2, or 3; other variables are as defined in this invention.

[0038] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a and R 2b Together with the carbon atoms they are attached to, they form rings.

[0039] X 2a and X 2c One of them is selected from: NR4, N, O, or S, and the other is selected from: C(R4)2, CR4, NR4, N, O, or S;

[0040] X 2b Selected from CR4 or C(R4)2;

[0041] Each occurrence is independently selected from either a single bond or a double bond;

[0042] The condition is when X 2a and / or X 2c When it is O or S, it is related to X. 2a and / or X 2cConnected Selected from single bonds;

[0043] Each R4 group is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0044] Other variables are as defined in this invention.

[0045] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0046] Each R 4a R 4b R 4c Each of them is independently selected from: H, halogen, or C. 1-6 alkyl;

[0047] Other variables are as defined in this invention.

[0048] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0049] Each R 4a R 4b R 4c When they appear, they are each independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0050] Other variables are as defined in this invention.

[0051] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0052] In some embodiments of the present invention, R3 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 3a Selected from: H, halogen, OH, or oxo group (=O); R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0053] In some embodiments of the present invention, R3 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 3a Selected from: H, F, Cl, Br, I, OH, or oxo group (=O); R 3b Selected from:

[0054] R 6a R 6b R 6c R 6d R 6e Each of the following is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0055] In some embodiments of the present invention, R3 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein:

[0056] R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0057] In some embodiments of the present invention, R3 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 3b Selected from:

[0058] R 6a R 6b R 6c R 6d R 6e Each of the following is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0059] In some embodiments of the present invention, R3 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 3c Selected from: H, or OH; X 3a X 3b X 3c X 3d X 3e Any one of them is selected from NR7 or O independently, and the rest are selected from C(R7)2 or X. 3a X 3b X 3c X 3d X 3e All are selected from C(R7)2, or X 3a X 3b X 3d X 3e All selected from CH2, X 3c The R7 is selected from C(R7)2; each of the R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0060] In some embodiments of the present invention, R3 is selected from the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein: R 3c Selected from: H, or OH; X 3a With X 3b Formation of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, X 3c X 3d X 3eThe R7 is selected from C(R7)2; each of the R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0061] In some embodiments of the present invention, the compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0062] R1 is selected from:

[0063] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, isopropyl;

[0064] m is selected from 0, 1, 2, or 3;

[0065] R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0066] Each R 4a R 4b R 4c Each of them is independently selected from: H, halogen, or C. 1-6 Alkyl; further preferably from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0067] Y2 is selected from: CR 2c 、 or N;

[0068] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0069] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0070] R3 is selected from:

[0071] R 3c Selected from: H, or OH;

[0072] X 3a X 3b X 3c X 3d X 3e Any one of them is selected from NR7 or O independently, and the rest are selected from C(R7)2 or X. 3aX 3b X 3c X 3d X 3e All are selected from C(R7)2, or X 3a X 3b X 3d X 3e All selected from CH2, X 3c Selected from C(R7)2;

[0073] R 5a and R 5b Each is independently selected from H, F, Cl, Br, I, OH, or R. 5a R 5b Together with the carbon atoms they are attached to, they form a cyclopropyl group;

[0074] R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0075] In one aspect of the invention, compounds of formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives are provided:

[0076]

[0077] in,

[0078] R1 is selected from:

[0079] R 1a and R 1b Each is independently selected from: H, or C 1-6 alkyl;

[0080] m is selected from 0, 1, 2, or 3;

[0081] n is selected from 0, 1, 2, or 3;

[0082] R 2a Selected from: H, or OH;

[0083] R 2b Selected from: H, or OH;

[0084] Or R 2a and R 2b Together with the carbon atoms they are attached to, they form rings.

[0085] X 2a and X 2cOne of them is selected from: NR4, N, O, or S, and the other is selected from: C(R4)2, CR4, NR4, N, O, or S.

[0086] X 2b Selected from CR4 or C(R4)2;

[0087] Each occurrence is independently selected from either a single bond or a double bond;

[0088] The condition is when X 2a and / or X 2c When it is O or S, it is related to X. 2a and / or X 2c Connected Selected from single bonds;

[0089] Each R4 is independently selected from: H, halogen, or C. 1-6 alkyl;

[0090] Y2 is selected from: CR 2c 、 or N;

[0091] R 2c Selected from: H, halogen, or C 1-6 alkyl;

[0092] R 2d Selected from: H, halogen, or C 1-6 alkyl;

[0093] R3 is selected from:

[0094] R 3a Selected from: H, halogen, OH, or oxo group (=O);

[0095] R 3b Selected from: C 3-10 cycloalkyl, C 6-10 Aryl, or 5-6 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl or 5-6 heteroaryl group is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0096] R 3c Selected from: H, or OH;

[0097] X 3a X 3b X 3c X 3d X 3e Each is independently selected from C(R7)2, NR7, or O;

[0098] Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being C(R7)2;

[0099] R 5a and R 5b Each is independently selected from H, halogen, OH, or R. 5a R 5b Together with the carbon atoms they are attached to, they form a cyclopropyl group;

[0100] R6 is selected from: H, halogens, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0101] R7 is independently selected from: H, halogen, C 1-6 Alkyl, or C 1-6 Alkyl group.

[0102] In some embodiments of the invention, R1 is selected from the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, isopropyl; m is selected from 0, 1, 2, or 3; other variables are as defined in this invention.

[0103] In some embodiments of the invention, R1 is selected from the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: R 1a Selected from: H, methyl, ethyl, n-propyl, isopropyl; m is selected from 0, 1, 2, or 3; other variables are as defined in this invention.

[0104] In some embodiments of the invention, in the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a and R 2b Together with the carbon atoms they are attached to, they form rings.

[0105] X 2a and X 2c One of them is selected from: NR4, N, O, or S, and the other is selected from: C(R4)2, CR4, NR4, N, O, or S;

[0106] X 2b Selected from CR4 or C(R4)2;

[0107] Each occurrence is independently selected from either a single bond or a double bond;

[0108] The condition is when X 2a and / or X 2c When it is O or S, it is related to X. 2a and / or X 2c Connected Selected from single bonds;

[0109] Each R4 group is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0110] Other variables are as defined in this invention.

[0111] In some embodiments of the invention, in the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0112] Each R 4a R 4b R 4c Each of them is independently selected from: H, halogen, or C. 1-6 alkyl;

[0113] Other variables are as defined in this invention.

[0114] In some embodiments of the invention, in the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0115] Each R 4a R 4b R 4c When they appear, they are each independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0116] Other variables are as defined in this invention.

[0117] In some embodiments of the invention, in the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0118] In some embodiments of the invention, R3 is selected from the following compounds represented by formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: R 3a Selected from: H, halogen, OH, or oxo group (=O); R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0119] In some embodiments of the invention, R3 is selected from the following compounds represented by formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: R 3a Selected from: H, F, Cl, Br, I, OH, or oxo group (=O); R 3b Selected from:

[0120] R 6a R 6b R 6c R 6d R 6e Each of the following is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0121] In some embodiments of the invention, R3 is selected from the following compounds represented by formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0122] In some embodiments of the invention, R3 is selected from the following compounds represented by formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: R 3b Selected from:

[0123] R 6a R 6b R 6c R 6d R 6e Each of the following is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0124] In some embodiments of the invention, R3 is selected from the following compounds represented by formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: R 3c Selected from: H, or OH; X 3a X 3b X 3c X 3d X 3e Any one of them is selected from NR7 or O independently, and the rest are selected from C(R7)2 or X. 3a X 3b X 3c X 3d X 3e All are selected from C(R7)2, or X 3a X 3b X 3d X 3e All selected from CH2, X 3c The R7 is selected from C(R7)2; each of the R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0125] In some embodiments of the invention, R3 is selected from the following compounds represented by formula (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: R 3c Selected from: H, or OH; X3a With X 3b Formation of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, X 3c X 3d X 3e The R7 is selected from C(R7)2; each of the R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0126] In some embodiments of the invention, the compound represented by formula (IIA) or (IIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0127] R1 is selected from:

[0128] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, isopropyl;

[0129] m is selected from 0, 1, 2, or 3;

[0130] R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0131] Each R 4a R 4b R 4c Each of them is independently selected from: H, halogen, or C. 1-6 Alkyl; further preferably from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0132] Y2 is selected from: CR 2c 、 or N;

[0133] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0134] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0135] R3 is selected from:

[0136] R 3c Selected from: H, or OH;

[0137] X 3a X3b X 3c X 3d X 3e Any one of them is selected from NR7 or O independently, and the rest are selected from C(R7)2 or X. 3a X 3b X 3c X 3d X 3e All are selected from C(R7)2, or X 3a X 3b X 3d X 3e All selected from CH2, X 3c Selected from C(R7)2;

[0138] R 5a and R 5b Each is independently selected from H, F, Cl, Br, I, OH, or R. 5a R 5b Together with the carbon atoms they are attached to, they form a cyclopropyl group;

[0139] R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0140] In one aspect of the invention, compounds of formula (IIC) or (IID), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives are provided:

[0141]

[0142] in,

[0143] R1 is selected from:

[0144] R 1a and R 1b Each is independently selected from: H, or C 1-6 alkyl;

[0145] m is selected from 0, 1, 2, or 3;

[0146] n is selected from 0, 1, 2, or 3;

[0147] Y2 is selected from: CR 2c 、 or N;

[0148] R 2c Selected from: H, halogen, or C 1-6 alkyl;

[0149] R 2d Selected from: H, halogen, or C 1-6alkyl;

[0150] X 2a Selected from: NR 4a 、O、or S;

[0151] R 4a R 4b and R 4c Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0152] R 3b Selected from: C 3-10 cycloalkyl, C 6-10 Aryl, or 5-6 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl or 5-6 heteroaryl group is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0153] R 5b Selected from: H, halogens, OH;

[0154] R6 is selected from: H, halogens, C 1-6 Alkyl, or C 1-6 Alkyl group.

[0155] In some embodiments of the invention, R1 is selected from the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0156] In some embodiments of the invention, in the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 4a Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 4b Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 4c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0157] In some embodiments of the invention, in the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 5b Selected from: H, F, Cl, Br, I, OH; other variables are as defined in this invention.

[0158] In some embodiments of the invention, in the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5) R6; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0159] In some embodiments of the invention, in the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5) R6; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0160] In some embodiments of the invention, in the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0161] In some embodiments of the invention, in the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 3b Selected from:

[0162] R 6a R 6b R6c R 6d R 6e Each of the following is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0163] In some embodiments of the invention, the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0164] R1 is selected from:

[0165] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0166] m is selected from 0, 1, 2, or 3;

[0167] n is selected from 0, 1, 2, or 3;

[0168] Y2 is selected from: CR 2c 、 or N;

[0169] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0170] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0171] X 2a Selected from: NR 4a 、O、or S;

[0172] R 4a R 4b and R 4c Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0173] R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0174] R 5b Selected from: H, F, Cl, Br, I, OH;

[0175] R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0176] In some embodiments of the invention, the compound represented by formula (IIC) or (IID), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0177] R1 is selected from:

[0178] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0179] m is selected from 0, 1, 2, or 3;

[0180] n is selected from 0, 1, 2, or 3;

[0181] Y2 is selected from: CR 2c 、 or N;

[0182] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0183] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0184] X 2a Selected from: NR 4a 、O、or S;

[0185] R 4a R 4b and R 4c Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0186] R 3b Selected from:

[0187] R 5b Selected from: H, F, Cl, Br, I, OH;

[0188] R 6a R 6b R 6c R 6d R 6e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0189] In one aspect of the invention, compounds of formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives are provided:

[0190]

[0191] in,

[0192] R1 is selected from:

[0193] R 1a and R 1b Each is independently selected from: H, or C 1-6 alkyl;

[0194] m is selected from 0, 1, 2, or 3;

[0195] n is selected from 0, 1, 2, or 3;

[0196] Y2 is selected from: CR 2c 、 or N;

[0197] R 2c Selected from: H, halogen, or C 1-6 alkyl;

[0198] R 2d Selected from: H, halogen, or C 1-6 alkyl;

[0199] X 2a Selected from: NR 4a 、O、or S;

[0200] R 4a R 4b and R 4c Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0201] R 3b Selected from: C 3-10 cycloalkyl, C 6-10 Aryl, or 5-6 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl or 5-6 heteroaryl group is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0202] R 5b Selected from: H, halogen, or OH;

[0203] R6 is selected from: H, halogens, C 1-6 Alkyl, or C 1-6 Alkyl group.

[0204] In some embodiments of the present invention, R1 is selected from the compounds represented by formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives: R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0205] In some embodiments of the invention, in the compounds represented by formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives, R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 4a Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 4b Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 4c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0206] In some embodiments of the invention, in the compounds represented by formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives, R 5b Selected from: H, F, Cl, Br, I, OH; other variables are as defined in this invention.

[0207] In some embodiments of the invention, in the compounds represented by formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives, R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5) R6; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0208] In some embodiments of the invention, in the compounds represented by formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives, R 3bSelected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0209] In some embodiments of the invention, in the compounds represented by formula (IIC-1), (IIC-2), (IID-1) or (IID-2), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives, R 3b Selected from:

[0210] R 6a R 6b R 6c R 6d R 6e Each of the following is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other variables are as defined in this invention.

[0211] In some embodiments of the invention, the compounds represented by formula (IIC-1), (IIC-2), (IID-1), or (IID-2), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives,

[0212] R1 is selected from:

[0213] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0214] m is selected from 0, 1, 2, or 3;

[0215] n is selected from 0, 1, 2, or 3;

[0216] Y2 is selected from: CR 2c 、 or N;

[0217] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0218] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0219] X 2a Selected from: NR 4a 、O、or S;

[0220] R 4a R 4b and R 4c Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0221] R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl phenyl, or pyridyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The phenyl or pyridyl group is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0222] R 5b Selected from: H, F, Cl, Br, I, OH;

[0223] R6 is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0224] In some embodiments of the invention, the compounds represented by formula (IIC-1), (IIC-2), (IID-1), or (IID-2), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives,

[0225] R1 is selected from:

[0226] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0227] m is selected from 0, 1, 2, or 3;

[0228] n is selected from 0, 1, 2, or 3;

[0229] Y2 is selected from: CR 2c 、 or N;

[0230] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0231] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0232] X 2a Selected from: NR 4a 、O、or S;

[0233] R 4a R 4b and R 4c Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0234] R 3b Selected from:

[0235] R 5b Selected from: H, F, Cl, Br, I, OH;

[0236] R 6a R 6b R 6c R 6d R 6e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0237] In one aspect of the invention, compounds of formula (III), pharmaceutically acceptable salts thereof, stereoisomers, or deuterated derivatives are provided:

[0238]

[0239] in,

[0240] R 1a R 1b R 1c R 1d Each is independently selected from: H, or C 1-6 alkyl;

[0241] R 2a Selected from: H, C 1-6 alkoxy group, or OH group;

[0242] R 2b R 2c R 2d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0243] X 3a X 3b X 3c X 3d X 3e Each is independently selected from CH2, NH, or O;

[0244] Or X 3a With X 3b， X 3b With X3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being CH2.

[0245] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 1a R 1b R 1c R 1d Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0246] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a Selected from: H, methoxy, ethoxy, n-propoxy, isopropoxy, or OH; other variables are as defined in this invention.

[0247] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2b R 2c R 2d Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0248] In some embodiments of the present invention, the compound represented by formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0249] In some embodiments of the present invention, the compound represented by formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0250] R 1a Each is independently selected from: methyl, ethyl, n-propyl, or isopropyl;

[0251] R 1b R 1c R 1d Each is independently selected from: H;

[0252] R 2a Selected from: methoxy, ethoxy, n-propoxy, isopropoxy, or OH;

[0253] R 2b R 2c R 2dEach is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0254] X 3a X 3b X 3c X 3d X 3e Each is independently selected from CH2, NH, or O;

[0255] Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being CH2.

[0256] In one aspect of the invention, compounds of formula (IIIA) or (IIIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives are provided:

[0257]

[0258] in,

[0259] R 1a R 1b R 1c R 1d Each is independently selected from: H, or C 1-6 alkyl;

[0260] R 2a Selected from: H, C 1-6 alkoxy group, or OH group;

[0261] R 2b R 2c R 2d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0262] X 3a X 3b X 3c X 3d X 3e Each is independently selected from CH2, NH, or O;

[0263] Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being CH2.

[0264] In some embodiments of the invention, in the compound represented by formula (IIIA) or (IIIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 1a R 1b R 1c R 1d Each is independently selected from: H, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0265] In some embodiments of the invention, in the compound represented by formula (IIIA) or (IIIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2a Selected from: H, methoxy, ethoxy, n-propoxy, isopropoxy, or OH; other variables are as defined in this invention.

[0266] In some embodiments of the invention, in the compound represented by formula (IIIA) or (IIIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, R 2b R 2c R 2d Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined in this invention.

[0267] In some embodiments of the invention, the compound represented by formula (IIIA) or (IIIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0268] In some embodiments of the invention, the compound represented by formula (IIIA) or (IIIB), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative,

[0269] R 1a Each is independently selected from: methyl, ethyl, n-propyl, or isopropyl;

[0270] R 1b R 1c R 1d Each is independently selected from: H;

[0271] R 2a Selected from: methoxy, ethoxy, n-propoxy, isopropoxy, or OH;

[0272] R 2b R 2c R 2dEach is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0273] X 3a X 3b X 3c X 3d X 3e Each is independently selected from CH2, NH, or O;

[0274] Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being CH2.

[0275] In another aspect of the invention, compounds, pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives thereof are provided as follows:

[0276]

[0277]

[0278] In another aspect of the invention, the invention provides pharmaceutically acceptable salts of the aforementioned compounds. The compounds of the invention are capable of forming acid addition salts and / or base addition salts. The acid addition salts can be formed with inorganic and organic acids, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and the organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.

[0279] This invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above, a pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof, and a pharmaceutically acceptable carrier. The carrier includes excipients conventional in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, or wetting agents.

[0280] The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, nasal sprays, transdermal patches, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally, via mucosal routes, rectally, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal routes). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type.

[0281] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The appropriate daily dose for human or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0282] The present invention further provides methods / uses of the said compound, its pharmaceutically acceptable salt, its stereoisomer, or pharmaceutical compositions thereof as medicines. The said compound, its pharmaceutically acceptable salt, its stereoisomer, or pharmaceutical compositions thereof can prevent, treat, or improve the pathology and / or symptoms of diseases in animals or humans.

[0283] In one aspect, the compounds of the present invention, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof exhibit significant inhibitory activity against the reuptake of at least one or more monoamine neurotransmitters (particularly dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Further, the compounds of the present invention, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof all exhibit significant inhibitory activity against the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT).

[0284] In another aspect, the compounds of the present invention, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof exhibit significant affinity and modulatory (e.g., agonist or inhibitory) activity toward the Sigma-1 receptor (i.e., σ-1R, or S1R). Furthermore, the compounds of the present invention, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof exhibit significant modulatory (e.g., agonist or inhibitory) activity toward the Sigma-1 receptor (i.e., σ-1R, or S1R) and contribute to improving or promoting neuroprotection, neurogenesis (neuronal generation), prevention, treatment, and relief of pain management, and stimulant addiction / substance abuse in patients.

[0285] In another aspect, the present invention provides the use / method of any of the compounds described above, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof for the prevention, treatment, or relief of patients with dopamine, norepinephrine, serotonin, and / or Sigma-1 receptor-mediated diseases.

[0286] This invention provides the use / method of any of the compounds described above, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof as monoamine neurotransmitter triple reuptake inhibitors and / or Sigma-1 receptor modulators for the prevention, treatment, and relief of CNS disorders, CNS diseases, and / or one or more related symptoms in patients. Furthermore, this invention provides the use / method of preventing, treating, and relieving CNS disorders, CNS diseases, and / or one or more related symptoms in patients by administering an effective amount of the compounds of this invention, their pharmaceutically acceptable salts, their stereoisomers, or pharmaceutical compositions thereof to a subject. The dopamine, norepinephrine, serotonin, and / or Sigma-1 receptor-mediated diseases, CNS disorders, CNS diseases and / or one or more of their related symptoms include, but are not limited to: attention deficit hyperactivity disorder (ADHD), depression, generalized anxiety disorder, pain management, fibromyalgia, neuropathic pain, schizophrenia, eating behaviors, Parkinson's syndrome, Alzheimer's disease, cognitive impairment, Rett syndrome, Fragile X syndrome, epilepsy, multiple sclerosis, narcolepsy, substance addiction / abuse, obesity, sleep disorders, panic disorder, bipolar disorder, dissociative disorder, post-traumatic stress disorder, obsessive-compulsive disorder, social anxiety disorder, autism, stimulant addiction / substance abuse, drug abuse tendency, nicotine abuse, tobacco abuse, cocaine abuse, alcohol addiction, sexual dysfunction, osteoporosis, menopausal symptoms, metabolic and eating disorders, amyotrophic lateral sclerosis, stroke, bone metabolism regulation, etc.

[0287] Definitions and Explanations

[0288] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0289] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0290] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, having specific substituents. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or acid addition salt.

[0291] 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 these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0292] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0293] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0294] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0295] The compounds of this invention contain one or more asymmetric centers (also called chiral centers), such as chiral carbons or chiral -SO- moieties. The stereochemistry of the chiral carbon centers present in the compounds of this invention is generally represented by the compound names and / or chemical structures shown herein. The compounds of this invention containing one or more chiral centers may exist as racemic mixtures, diastereomeric mixtures, enantiomer-enriched mixtures, diastereomeric-enriched mixtures, or as individual stereoisomers, either enantiomerically or diastereomeric. When two adjacent carbon atoms marked with an asterisk (*) are both chiral carbon atoms, each may exist as a single enantiomer (R) or (S) or enriched in one enantiomer, resulting in four stereoisomers (optical isomers): 1R,2R-, 1S,2S-, 1R,2S-, and 1S,2R-. When the preferred substituents of two adjacent carbon atoms are on the same side in the Fischer projection, it is a "erythro form," i.e., 1R,2R- and 1S,2S-. When the preferred substituents of two adjacent carbon atoms are on different sides in the Fischer projection, it is called the "threo form"; that is, 1R,2S- or 1S,2R-.

[0296] For example: in middle, The configuration is "erythroform". Mixtures and / or racemates of the two can be used... express; For a mixture and / or racemate of the two in the "threo form", it can be used express.

[0297] Unless otherwise stated, the term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0298] Unless otherwise stated, the term "geometric isomer" arises from the fact that double bonds or single bonds of cyclic carbon atoms cannot rotate freely.

[0299] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0300] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0301] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0302] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient, including but not limited to: adhesives, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0303] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0304] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms 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. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of an additional unlabeled reagent.

[0305] The term "deuterated analog" refers to an analog produced by replacing one or more hydrogen atoms of a compound with deuterium atoms. The terms "optional" or "optionally" refer to events or conditions described subsequently that may occur but are not required, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur. For example, "optionally substituted with one or more deuterium atoms" means that the group may be unsubstituted or substituted with one or more deuterium atoms, i.e., it includes cases where the group is unsubstituted, partially substituted, and / or fully substituted.

[0306] The terms “optional,” “optionally,” or “optionally replaced by…” mean that the event or situation subsequently described may, but is not necessarily, occur, and the description includes both the occurrence and non-occurrence of said event or situation. For example, “optionally replaced by…” means that a substituent may or may not be present, and that the substituent may include one, two, or three, etc.

[0307] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, which can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C 10 C represents 1 to 10 carbon atoms. 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of alkyl groups include, but are not limited to, 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), heptyl, octyl, nonyl, decyl, etc. Understandably, the term "alkylene" refers to a residue that has lost one hydrogen atom from an alkyl group. Examples of C1-C6 alkylene groups include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(CH3)-CH2, etc. It is important to note that when an alkylene group (e.g., methylene) appears at the end of a straight or branched chain or at the end of a substituent, it includes "CH2=", where the hydrogen atom can be replaced by one or two halogen atoms (e.g., fluorine atoms).

[0308] Unless otherwise specified, "halogen" on its own or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.

[0309] Unless otherwise specified, "alkoxy" is used to denote an alkyl group (including cycloalkyl or haloalkyl) with a specific number of carbon atoms connected by an oxygen bridge. Typical alkoxy groups include C0. 1-6Alkoxy groups, such as: C1, C2, C3, C4, C5, C6 alkoxy groups; C3, C4, C5, C6 cycloalkoxy groups; and C1, C2, C3, C4, C5, C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, and 2-ethylbutoxy. Examples of cycloalkoxy groups include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Examples of haloalkoxy groups include, but are not limited to: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0310] Unless otherwise specified, the term "cycloalkyl" is intended to include any stable cyclic or polycyclic hydrocarbon group in which all carbon atoms are saturated, and which may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent. For example, C 3-10 C represents 3 to 10 carbon atoms. 3-10 Selected from C3, C4, C5, C6, C7, C8, C9, C 10 Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornel, bicyclo[2.2.1]heptyl, [2.2.2]bicyclooctyl, [4.4.0]bicyclodecyl, 2,7,7-trimethylbicyclo[2.2.1]heptane-1-yl, tricyclo[3.3.1.1] 3,7 Decyl (adamantyl) and others.

[0311] Unless otherwise specified, "aryl" refers to an aromatic carbocyclic group with 6 to 10 carbon atoms, having a monocyclic or multiple fused rings. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0312] Unless otherwise specified, "5-6-membered heteroaryl" refers to a monovalent aromatic group with 5 to 6 ring atoms, having oxygen, nitrogen, and sulfur heteroatoms in one or more rings, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heteroaryl can have a monocyclic ring (e.g., pyridinyl or furanyl) or multiple fused rings, provided the connection point is via a heteroaryl ring atom. Monocyclic heteroaryls generally comprise 5- or 6-membered aromatic rings, and examples of monocyclic heteroaryls include pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrroleyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thiopheneyl, furanyl, pyrroleyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, and pyrazolyl.

[0313] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0314] The present invention will be further illustrated below with reference to specific embodiments and test examples, but this does not limit the scope of the invention in any way.

[0315] In the following embodiments, the following reagent abbreviations have the following meanings. If not defined, they are said to have meanings generally accepted in the art.

[0316] abbreviation Reagent meaning / Chinese name HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate LiHMDS Lithium bis(trimethylsilyl)amino DBU 1,8-Diazozyne-bisspirocyclic[5.4.0]undec-7-ene DMF N,N-Dimethylformamide DIEA N,N-Diisopropylethylamine dppf 1,1′-Ferrocene di-bis(diphenylphosphine) LDA Lithium diisopropylaminodimethylamine TBAF Tetrabutylammonium fluoride Selectfluor reagent 1-Chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) NIS N-Iodosuccinimide

[0317] Example 1

[0318]

[0319] Step 1: Synthesis of compounds 1-3

[0320] Compound 1-1 (3 g, 19.71 mmol) and compound 1-2 (7.04 g, 19.71 mmol) were dissolved in tetrahydrofuran (90 mL). Lithium di(trimethylsilyl)amino (19.71 mL) was added dropwise at -78 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 hours. After the reaction was completed by TLC monitoring, ethyl acetate (50 mL) and saturated NH4Cl (100 mL) were added to the reaction mixture. The mixture was extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed once with 20 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 1 / 0) to give compound 1-3 (6.85 g, yield 91.82%, colorless oil). The product was used directly in the next reaction under nitrogen protection.

[0321] Step 2: Synthesis of compounds 1-4

[0322] Compounds 1-3 (6.35 g, 22.34 mmol), palladium acetate (401.17 mg, 1.79 mmol), N,N-diisopropylethylamine (8.66 g, 67.01 mmol), and dppf (990.61 mg, 1.79 mmol) were dissolved in N,N-dimethylformamide (35 mL) and methanol (9 mL) under nitrogen protection. After three purgings with carbon monoxide, the mixture was stirred at 60 °C for 12 hours under a carbon monoxide (50 psi) atmosphere. After the reaction was completed by TLC monitoring, ethyl acetate (30 mL) and water (50 mL) were added to the reaction solution. The mixture was extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed once with 10 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 1 / 0) to give compounds 1-4 (3.4 g, yield 78.36%, colorless oil).

[0323] Step 3: Synthesis of compounds 1-5

[0324] Compounds 1-4 (3.4 g, 17.50 mmol) and sodium hydroxide solution (1 M, 40 mL) were dissolved in methanol (160 mL). The reaction mixture was stirred at 70 °C for 12 hours. After the reaction was completed by LCMS monitoring, the crude product was concentrated under reduced pressure. Ethyl acetate (30 mL) and water (50 mL) were added, and the mixture was extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compounds 1-5 (2.3 g, 72.91% yield, white solid).

[0325] Step 4: Synthesis of compounds 1-7

[0326] Compounds 1-5 (0.5 g, 2.77 mmol), compounds 1-6 (730.61 mg, 2.77 mmol), and 4-dimethylaminopyridine (16.94 mg, 138.70 μmol) were dissolved in dichloromethane (10 mL). N,N-dicyclohexylcarboimide (686.83 mg, 3.33 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was purified by reverse-phase separation (0.05% formic acid system and 25-55% acetonitrile) to give compounds 1-7 (1.3 g, yield 99.10%, white solid).

[0327] Step 5: Synthesis of Compound 1

[0328] Compounds 1-7 (500 mg, 1.06 mmol) were dissolved in tetrahydrofuran (10 mL), and palladium on carbon was added under a nitrogen atmosphere. After three purgings with hydrogen, the mixture was stirred at 30 °C for 2 hours under a hydrogen balloon atmosphere (15 psi). After the reaction was complete as monitored by LCMS, the reaction solution was purified by reverse-phase separation (0.05% ammonia solution and 28-58% acetonitrile) to give compound 1 (22.61 mg, white solid, yield 4.93%). LCMS: 428.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ = 7.21 (d, J = 8.5Hz, 2H), 7.04 (d, J = 8.5Hz, 2H), 4.05 (dd, J = 4.6, 12. 7Hz,1H),3.45(t,J=4.8Hz,1H),3.11(dd,J=5.1,12.8Hz,1H),2.92-2.66(m,6H),2.63(br d,J=9.0Hz,1H),2.41-2.27(m,1H),1.87-1.79(m,2H),1.72(br dd,J=14.0,17.8Hz,2H),1.66-1.54(m,4H),1.52-1.43(m,3H),1.42-1.30(m,2H),1.29-1.22(m,1H),1.18-1.07(m,4H),0.97-0.84(m,6H).

[0329] Example 2

[0330]

[0331]

[0332] Step 1: Synthesis of Compound 2-2

[0333] Starting material 2-1 (2 g, 11.22 mmol) and dimethylamine hydrochloride (1.83 g, 22.71 mmol) were dissolved in N,N-dimethylformamide (20 mL). N,N-diisopropylethylamine (5.80 g, 44.90 mmol) was added at room temperature, followed by the addition of HATU (5.12 g, 13.47 mmol) in portions at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed as monitored by mass spectrometry, the crude product was purified by reverse-phase separation (0.1% formic acid system and 80-90% acetonitrile) to give compound 2-2 (2 g, yellow oil, yield 86.81%).

[0334] Step 2: Synthesis of compounds 2-4

[0335] Compound 2-4 (1.8 g, 9.35 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) under nitrogen protection. The solution was cooled to -78 °C, and lithium di(trimethylsilyl)amino (1 M, 13.15 mL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. Compound 2-3 (1.72 g, 17.54 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and added dropwise to the reaction mixture at -78 °C under N2 protection. After the addition was complete, the mixture was stirred at -78 °C for 2 hours. After the reaction was monitored by LCMS, the reaction solution was slowly poured into water (500 mL), the pH was adjusted to 4 with 3N hydrochloric acid aqueous solution, and then 200 mL of ethyl acetate was added for extraction three times. The combined organic phases were washed once with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 3 / 1-1 / 1) to give compound 2-4 (2.6 g, yield 97.72%, white solid).

[0336] Step 3: Synthesis of Compound 2

[0337] Compounds 2-4 (500 mg, 1.65 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL), and lithium aluminum hydride (2.5 M, 2.31 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction mixture was cooled to 0 °C, sodium sulfate decahydrate was added until the reaction mixture stopped bubbling, and then 50 mL of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% ammonium bicarbonate system and 26-56% acetonitrile) to obtain compound 2 (400 mg, white solid, yield 81.35%). Compound 2A (retention time: 1.624 min) and compound 2B (retention time: 1.817 min) were separated by SFC (column type: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode).

[0338] Compound 2A: LCMS: 290.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ = 6.99 (s, 1H), 6.92-6.87 (m, 1H), 6.72 (d, J = 8.2Hz, 1H), 4.59 (t, J = 8.7Hz, 2H), 3.36-3.18 (m, 3H), 2. 96(dd,J=3.2,12.4Hz,1H),2.44-2.26(m,7H),1.85-1.66(m,3H),1.64-1.52(m,3H),1.45-1.30(m,2H),1.09-0.85(m,2H).

[0339] Compound 2B: LCMS: 290.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 6.97 (s, 1H), 6.87 (dd, J = 1.6, 8.2Hz, 1H), 6.69 (d, J = 8.1Hz, 1H), 4.56 (t, J = 8.6Hz, 2H), 3.32-3.16 (m, 3H ), 2.93 (dd, J = 3.3, 12.4Hz, 1H), 2.38-2.25 (m, 7H), 1.79-1.64 (m, 3H), 1.61-1.50 (m, 3H), 1.42-1.27 (m, 2H), 1.05-0.85 (m, 2H).

[0340] Compounds 47-50, 57, 61-62, and 69 were obtained using the same synthetic method as compound 2. The characterization data of each compound are shown in the table below:

[0341]

[0342]

[0343] Example 3

[0344]

[0345]

[0346] Compound 5 was synthesized using the same method as compound 2. Compound 5A (retention time: 1.395 min) and compound 5B (retention time: 1.491 min) were obtained by resolution using SFC (column type: DAICELCHIRALPAK IC (250 mm × 50 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode).

[0347] Compound 5A: LCMS: 292.2 [M+H] + .1 H NMR (400MHz, CDCl3) δ = 6.69 (d, J = 8.0Hz, 1H), 6.62-6.51 (m, 2H), 5.90 (s, 2H), 3.18 (t, J = 12.4Hz, 1H), 2. 88(dd,J=3.4,12.3Hz,1H),2.39-2.13(m,7H),1.80-1.43(m,6H),1.40-1.19(m,2H),1.02-0.80(m,2H).

[0348] Compound 5B: LCMS: 292.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 6.73 (d, J = 7.9Hz, 1H), 6.67-6.57 (m, 2H), 5.94 (s, 2H), 3.26 (br t, J = 12.3Hz, 1H), 2.94 (br dd,J=3.3,11.8Hz,1H),2.34(s,7H),1.77-1.64(m,3H),1.62-1.50(m,3H),1.44-1.28(m,2H),1.07-0.86(m,2H).

[0349] Example 4

[0350]

[0351] Step 1: Synthesis of Compound 6-3

[0352] Compound 6-1 (5 g, 18.56 mmol) was dissolved in tetrahydrofuran (100 mL). After purging with nitrogen three times, the reaction solution was cooled to -78 °C. Lithium di(trimethylsilyl)amino (18.56 mL, 18.56 mmol) was slowly added dropwise under a nitrogen atmosphere. The mixture was reacted at this temperature for 1 hour, followed by the addition of compound 6-2 (12.57 g, 55.69 mmol). The mixture was then reacted at this temperature for another hour. After the reaction was completed as monitored by LCMS, ethyl acetate (100 mL) and water (200 mL) were added to the reaction solution. The aqueous phase was extracted three times with 80 mL of ethyl acetate. The combined organic phases were washed once with 50 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 10 / 0-0 / 1) to give compound 6-3 (6 g, yield 67.66%, white solid).

[0353] Step 2: Synthesis of compound 6-4

[0354] Compound 6-3 (1 g, 2.18 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction temperature was then lowered to 0 °C, and lithium aluminum hydride solution (2.62 mL, 6.54 mmol) was slowly added dropwise. The reaction was then heated to 70 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was cooled to 0 °C, and sodium sulfate decahydrate solid was slowly added in portions until no more bubbles were generated. The mixture was stirred at this temperature for half an hour, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation (0.1% trifluoroacetic acid system and 10-40% acetonitrile) to obtain compound 6-4 (680 mg, colorless gel, yield 68.55%).

[0355] Step 3: Synthesis of Compound 6

[0356] Compound 6-4 (50 mg, 0.112 mmol) was dissolved in methanol (3 mL). Palladium on carbon was added under a nitrogen atmosphere, and the mixture was purged three times with hydrogen. The mixture was then stirred at 25 °C for 0.5 h under a hydrogen balloon atmosphere (15 psi). After the reaction was completed as monitored by LCMS, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 6 (26.82 mg, colorless oil, yield 85.70%). LCMS: 265.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ = 7.21 (br d, J = 8.0Hz, 2H), 6.85 (br dd,J=3.7,7.9Hz,2H),3.67-3.40(m,2H),3.30-3.10(m,3H),2.96-2.80(m,1H),2.77-2.67(m,7H),2.13-1.49(m,4H).

[0357] Example 5

[0358]

[0359] Step 1: Synthesis of Compound 7-3

[0360] Compound 7-1 (2 g, 7.43 mmol) and compound 7-2 (1.69 g, 14.85 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL) under nitrogen protection. Lithium bis(trimethylsilyl)amino (1 M, 18.56 mL) was added dropwise at 50 °C, and the mixture was stirred at 50 °C for 2 hours after the addition was complete. After the reaction was monitored by LCMS, the reaction mixture was slowly poured into a saturated ammonium chloride aqueous solution (300 mL), and then extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed once with 100 mL of 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 (silica gel column, dichloromethane / methanol = 10 / 1) to give compound 7-3 (1.4 g, yield 53.34%, yellow solid).

[0361] Step 2: Synthesis of compound 7-4

[0362] Compound 7-3 (1.2 g, 3.46 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and the solution was cooled to 0 °C. Borane dimethyl sulfide solution (10 M, 2.08 mL) was added dropwise. After the addition was complete, the mixture was stirred at 70 °C for 16 hours. After the reaction was completed by LCMS monitoring, methanol was slowly added dropwise until no more bubbles appeared, and then another 10 mL of methanol was added. The reaction mixture was then stirred at 70 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase separation (0.1% trifluoroacetic acid system and 20%-50% acetonitrile) to give compound 7-4 (870 mg, yield 75.55%, yellow oil).

[0363] Step 3: Synthesis of compounds 7-5

[0364] Compound 7-4 (770 mg, 2.32 mmol) was dissolved in methanol (10 mL). Under argon protection, palladium on carbon (246.49 mg, 0.23 mmol) was added, and the mixture was purged three times with hydrogen. The mixture was then stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 psi). After the reaction was completed as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reverse-phase separation (0.1% formic acid system and 1%-25% acetonitrile) to obtain compound 7-5 (500 mg, white solid, yield 87.3%). The crude product was used directly in the next reaction step.

[0365] Step 4: Synthesis of Compound 7

[0366] Compound 7-5 (500 mg, 2.06 mmol) was dissolved in ethanol (15 mL). Platinum dioxide and hydrochloric acid (0.1 mL, 2.06 mmol) were added under argon protection. After three purgings with hydrogen, the mixture was stirred at 25 °C for 2 hours under a hydrogen atmosphere (25 psi). After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reverse-phase separation (0.1% hydrochloric acid system and 0% acetonitrile) to give compound 7 (168 mg, colorless gel, yield 31.14%). LCMS: 249.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ = 7.43-7.21 (m, 2H), 6.95 (dd, J = 8.4, 15.2Hz, 2H), 3.89-3.60 (m, 2H), 3. 58-3.33(m,3H),3.13-2.90(m,1H),2.90-2.77(m,6H),2.24-1.92(m,1H),1.88-1.26(m,5H).

[0367] Example 6

[0368]

[0369] Step 1: Synthesis of Compound 8-2

[0370] Compound 6-3 (1 g, 2.18 mmol) was dissolved in dichloromethane (50 mL), and thionyl chloride (2.59 g, 21.81 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 20-50% acetonitrile) to give compound 8-2 (410 mg, yellow solid, yield 41.82%).

[0371] Step 2: Synthesis of compound 8-3

[0372] Compound 8-2 (300 mg, 0.68 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction temperature was then lowered to 0 °C, and lithium aluminum hydride solution (0.82 mL, 2.04 mmol) was slowly added dropwise. The reaction was then heated to 70 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was cooled to 0 °C, and sodium sulfate decahydrate solid was slowly added in portions until no more bubbles were generated. The mixture was stirred at this temperature for half an hour, filtered, and concentrated under reduced pressure to obtain compound 8-3 (190 mg, colorless oil, yield 64.10%).

[0373] Step 3: Synthesis of Compound 8

[0374] Compound 8-3 (190 mg, 0.445 mmol) was dissolved in methanol (8 mL). Palladium on carbon was added under a nitrogen atmosphere, and the mixture was purged three times with hydrogen. The mixture was then stirred at 25 °C for 0.5 h under a hydrogen balloon atmosphere (15 psi). After the reaction was completed as monitored by LCMS, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% hydrochloric acid system and 0-15% acetonitrile) to give compound 8 (53 mg, colorless oil, yield 45.52%). LCMS: 249.2 [M+H] + . 1 H NMR(400MHz, CD3OD)δ=7.37-7.18(m,2H),6.98-6.86(m,2H),3.84-3.34(m,3H ),3.31-2.95(m,2H),2.93-2.49(m,8H),2.21-1.57(m,4H),1.54-1.09(m,1H).

[0375] Example 7

[0376]

[0377] Step 1: Synthesis of compound 9-3

[0378] Starting material 9-1 (10 g, 58.40 mmol) was dissolved in tetrahydrofuran (100 mL). Under N2 protection, starting material 9-2 (1 M, 75.92 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 hours. After the reaction was monitored by LCMS and TLC, the reaction mixture was slowly poured into water (500 mL), and then extracted three times with 200 mL of ethyl acetate. The combined organic phases were washed once with 300 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 10 / 1-9 / 1) to give compound 9-3 (9.03 g, yield 63.2%, yellow solid).

[0379] Step 2: Synthesis of compound 9-4

[0380] Compound 9-3 (9 g, 38.74 mmol) and dimethylamine hydrochloride (31.6 g, 387.4 mmol) were dissolved in anhydrous methanol (100 mL). Paraformaldehyde (34.9 g, 387.4 mmol) was added in portions, and the mixture was refluxed at 70 °C for 48 hours. After the reaction was completed by LCMS monitoring, anhydrous methanol (150 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 9-4 (9.23 g, yield 64.21%, yellow solid).

[0381] Step 3: Synthesis of Compound 9

[0382] Compound 9-4 (2 g, 6.91 mmol) was dissolved in dichloromethane (20 mL). Boron tribromide (2 M, 6.91 mL) was slowly added dropwise to the reaction solution at 0 °C, and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed as monitored by LCMS, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% hydrochloric acid system and 5-35% acetonitrile) to give compound 9 (585.5 mg, yield 27.17%, white solid). LCMS: 276.1 [M+H] + . 1 HNMR (400MHz, METHANOL-d4) δ = 7.14 (d, J = 8.4Hz, 2H), 6.84 (d, J = 8.3Hz, 2H), 4.45 (br t, J = 7.0Hz, 1H), 3.75 (br dd,J=8.4,13.0Hz,1H),3.35-3.31(m,1H),3.01-2.73(m,6H),2.56-2.31(m,1H),1.99(br d,J=6.9Hz,1H),1.76(br s,1H),1.62(br d,J=11.5Hz,2H),1.41-0.99(m,6H).

[0383] Example 8

[0384]

[0385] Step 1: Synthesis of Compound 10-2

[0386] 10⁻¹ (2 g, 11.35 mmol), HATU (5.18 g, 13.62 mmol), and DIEA (4.35 mL, 24.98 mmol) were dissolved in dimethylformamide (30 mL). Under N₂ protection, dimethylamine hydrochloride (1.02 g, 12.49 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 12 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was slowly poured into water (20 mL), and then extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed twice with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 10⁻² (1.3 g, yield 56.3%, brown oil).

[0387] Step 2: Synthesis of compound 10⁻⁴

[0388] Intermediate 10⁻² (0.6 g, 2.95 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL). Under N₂ protection, bis(trimethylsilyl)aminolithium (1 M, 5.9 mL) was added at -70 °C, and the mixture was stirred at -70 °C for 1 hour. Then, 10⁻³ (357.64 mg, 3.19 mmol) was added dropwise to the reaction mixture at -70 °C. After the addition was complete, the mixture was stirred at -70 °C for 3 hours. After the reaction was monitored by LCMS, 10 mL of saturated ammonium chloride aqueous solution was added dropwise to the reaction mixture, followed by extraction three times with 10 mL of ethyl acetate. The combined organic phases were washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain intermediate 10⁻⁴ (650 mg, yield 69.81%, colorless oil).

[0389] Step 3: Synthesis of Compound 10

[0390] Intermediate 10⁻⁴ (650 mg, 2.06 mmol) was dissolved in tetrahydrofuran (7 mL). Under N₂ protection, lithium aluminum hydride (2.5 M, 2.89 mL) was slowly added dropwise to the reaction solution at 0 °C. After the addition was complete, the temperature was raised to 70 °C and stirred for 12 hours. After the reaction was monitored by LCMS, the reaction solution was diluted with 10 mL of tetrahydrofuran. The reaction was quenched by adding 0.3 mL of water, 0.3 mL of 15% sodium hydroxide aqueous solution, and 0.9 mL of water sequentially. An appropriate amount of anhydrous sodium sulfate was then added, and the mixture was filtered through diatomaceous earth. The filtrate was collected and evaporated to dryness to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 10-40% acetonitrile) to give compound 10 (332.8 mg, yield 53.45%, grayish-white viscous gel). LCMS: 302.3 [M + H] + . 1 H NMR(400MHz,CHLOROFORM-d)δppm 8.57(s,1H),7.71(s,1H),7.62(d,J=2.0Hz,1H),7.45(m,1H),7.33(m,1H),6.75(m,1H),3.75-3.67(m,2H),3.2 9-3.27(m,1H),2.74(dd,J=12.40,4.80Hz,1H),2.67(s,6H),2.05(m,1H),1.71-1.54(m,4H),1.12–0.93(m,6H).

[0391] Compounds 34 and 68 were synthesized using the same method as compound 10. Characterization data for each compound are shown in the table below:

[0392]

[0393] Example 9

[0394]

[0395] Step 1: Synthesis of Compound 13-3

[0396] Starting materials 13-1 (0.5 g, 2.84 mmol) and 13-2 (0.29 g, 3.41 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (1.1 g, 8.51 mmol) was added at room temperature, followed by the addition of HATU (1.29 g, 3.41 mmol) in portions at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed as monitored by LCMS, the crude product was purified by reverse-phase separation (0.1% formic acid system and 80-90% acetonitrile) to give compound 13-3 (0.606 g, yellow oil, yield 87.76%).

[0397] Step 2: Synthesis of Compounds 13-5

[0398] Compound 13-3 (0.5 g, 2.06 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) under nitrogen protection. The solution was cooled to -78 °C, and lithium bis(trimethylsilyl)amino (1 M, 3.08 mL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. Starting material 13-4 (403.38 mg, 4.11 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and added dropwise to the reaction mixture at -78 °C under N2 protection. After the addition was complete, the mixture was stirred at -78 °C for 2 hours. After the reaction was monitored by LCMS, the reaction solution was slowly poured into water (200 mL), and the pH was adjusted to 4 with 3N hydrochloric acid aqueous solution. Then, 50 mL of ethyl acetate was added for extraction three times. The combined organic phases were washed once with 100 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 3 / 1-1 / 1) to give compound 13-5 (0.690 g, yield 98.33%, white solid).

[0399] Step 3: Synthesis of Compound 13

[0400] Compound 13-5 (300 mg, 0.878 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium aluminum hydride (2.5 M, 1.23 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction mixture was cooled to 0 °C, sodium sulfate decahydrate was added until the reaction mixture stopped bubbling, and then 50 mL of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 15-45% acetonitrile) to obtain compound 13 (160 mg, white solid, yield 55.61%).

[0401] Step 4: Synthesis of Compound 13A

[0402] Compound 13 was separated under the following conditions: column type: DAICL CHIRALPAK IG (250 mm × 50 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode to give compound 13A (retention time: 1.085 min, 73.18 mg, yellow oil, yield 73.18%). LCMS: 328.3 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ = 7.81 (d, J = 2.1Hz, 1H), 7.67 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.33 (br d,J=8.1Hz,1H),6.89(d,J=1.3Hz,1H),3.81(dd,J=4.9,13.3Hz,1H),3.57(br dd,J=9.1,13.0Hz,1H),3.30-3.06(m,4H),1.89-1.24(m,16H),1.15-0.99(m,1H).

[0403] Step 5: Synthesis of Compound 13B

[0404] Compound 13 was separated under the following conditions: column type: DAICL CHIRALPAK IG (250 mm × 50 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode to give compound 13B (retention time: 1.162 min, 59.74 mg, yellow oil, yield 60%). LCMS: 328.32 [M+H] + . 1H NMR (400MHz, METHANOL-d4) δ = 7.65 (d, J = 2.1Hz, 1H), 7.37 (d, J = 0.7Hz, 1H), 7.33 (d, J = 8.6Hz, 1H), 7.06 (dd,J=1.3,8.6Hz,1H),6.73(d,J=1.5Hz,1H),3.28-3.25(m,1H),3.05(dd,J=4.2,11.1Hz,1H),2.62(br s,2H),2.41(dd,J=4.2,13.0Hz,1H),2.33(br s,2H),1.76-1.17(m,15H),0.93(dt,J=4.2,13.3Hz,1H),0.86-0.71(m,1H).

[0405] Example 10

[0406]

[0407]

[0408] Step 1: Synthesis of Compound 14-3

[0409] Starting materials 14-1 (500 mg, 2.84 mmol), 14-2 (243 mg, 3.41 mmol), and N,N-diisopropylethylamine (1.1 g, 8.51 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was cooled to 0 °C, and then HATU (1.29 g, 3.41 mmol) was added in portions. The mixture was reacted at 0 °C for 2 hours. After the reaction was completed by LCMS monitoring, ethyl acetate (30 mL) and water (50 mL) were added to the reaction solution. The aqueous phase was extracted three times with 30 mL of ethyl acetate. The combined organic phases were washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 78-90% acetonitrile) to give compound 14-3 (595 g, yield 91.44%, white solid).

[0410] Step 2: Synthesis of Compounds 14-5

[0411] Compound 14-3 (420 mg, 1.83 mmol) was dissolved in tetrahydrofuran (15 mL). After purging with nitrogen three times, the reaction solution was cooled to -78 °C. Under a nitrogen atmosphere, lithium di(trimethylsilyl)amino (2.75 mL, 2.75 mmol) was slowly added dropwise, and the mixture was reacted at this temperature for 1 hour. Compound 14-4 (360 mg, 3.66 mmol) was dissolved in tetrahydrofuran (5 mL) and slowly added to the reaction solution. The mixture was then reacted at this temperature for another hour. After the reaction was completed as monitored by LCMS, water (80 mL) was added to the reaction solution, and the pH was adjusted to 5-6 with 2 M dilute hydrochloric acid. Extracted three times with 30 mL of ethyl acetate, the combined organic phases were washed once with 30 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 10 / 0-3 / 1) to give compound 14-5 (580 mg, yield 96.70%, yellow solid).

[0412] Step 3: Synthesis of Compound 14

[0413] Compound 14-5 (300 mg, 0.92 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction temperature was then lowered to 0 °C, and lithium aluminum hydride solution (1.28 mL, 3.21 mmol) was slowly added dropwise. The reaction was then heated to 70 °C for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was cooled to 0 °C, and sodium sulfate decahydrate solid was slowly added in portions until no more bubbles were generated. The mixture was stirred at this temperature for half an hour, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 12-42% acetonitrile) to obtain compound 14 (100 mg, yield 34.82%, white solid).

[0414] Step 4: Synthesis of Compound 14A

[0415] Compound 14 was separated under the following conditions: column type: DAICL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode to give compound 14A (retention time: 1.194 min, 26.10 mg, white solid, yield 24.80%). LCMS: 314.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ (ppm) = 7.63 (d, J = 2.1Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.5Hz, 1H), 7.11 (br d, J = 8.4Hz, 1H), 6.71 (d, J = 1.3Hz, 1H), 3.48 (br dd,J=6.9,12.3Hz,1H),2.95(br t,J=7.2Hz,1H),2.92-2.83(m,1H),2.73-2.54(m,4H),1.70(br s,4H),1.62-1.49(m,3H),1.49-1.33(m,4H),1.29(br s,1H),1.13-1.02(m,1H),0.98-0.80(m,1H).

[0416] Step 5: Synthesis of Compound 14B

[0417] Compound 14 was separated under the following conditions: column type: DAICL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode to give compound 14B (retention time: 1.311 min, 26.64 mg, white solid, yield 26.37%). LCMS: 314.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ (ppm) = 7.72 (d, J = 2.1Hz, 1H), 7.52 (d, J = 1.3Hz, 1H), 7.43 (d, J = 8.5Hz, 1H), 7.21 (dd, J =1.6,8.6Hz,1H),6.81(dd,J=0.9,2.1Hz,1H),3.57(dd,J=7.3,12.4Hz,1H),3.05(t,J=7.3Hz,1H),2.93(br dd,J=7.6,11.2Hz,1H),2.84-2.56(m,4H),1.79(br s,4H),1.69-1.45(m,6H),1.38(br d,J=4.1Hz,1H),1.35-1.28(m,1H),1.23-1.11(m,1H),1.05-0.90(m,1H).

[0418] Example 11

[0419]

[0420] Step 1: Synthesis of Compound 15-3

[0421] Starting materials 15-1 (500.00 mg, 2.84 mmol) and 15-2 (318.63 mg, 3.41 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (1.83 g, 14.19 mmol) was added at room temperature, followed by the addition of HATU (1.29 g, 3.41 mmol) in portions at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 78-90% acetonitrile) to obtain compound 15-3 (532 mg, white solid, yield 87.08%).

[0422] Step 2: Synthesis of Compound 15-5

[0423] Compound 15-3 (100 mg, 464.58 μmol) was dissolved in anhydrous tetrahydrofuran (4 mL) under nitrogen protection. The solution was cooled to -78 °C, and lithium di(trimethylsilyl)amino (1 M, 696.87 μL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. Starting material 15-4 (91.19 mg, 929.16 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and added dropwise to the reaction mixture at -78 °C under N2 protection. After the addition was complete, the mixture was stirred at -78 °C for 2 hours. After the reaction was monitored by LCMS and TLC, the reaction solution was slowly poured into water (200 mL), the pH was adjusted to 4 with 3N hydrochloric acid aqueous solution, and then 50 mL of ethyl acetate was added for extraction three times. The combined organic phases were washed once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 3 / 1-2 / 1) to give compound 15-5 (140 mg, yield 95.20%, white solid).

[0424] Step 3: Synthesis of Compound 15

[0425] Compound 15-5 (140 mg, 446.73 μmol) was dissolved in anhydrous tetrahydrofuran (8 mL), and lithium aluminum hydride solution (2.5 M, 625.42 μL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour. After the reaction was completed by LCMS and TLC monitoring, the reaction mixture was cooled to 0 °C, sodium sulfate decahydrate was added until the reaction mixture stopped bubbling, and then 20 mL of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% hydrochloric acid system and 15-45% acetonitrile) to obtain compound 15 (80 mg, white gel, yield 59.81%).

[0426] Step 4: Synthesis of Compound 15A

[0427] Compound 15 was separated under the following conditions: column type: DAICL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode to give compound 15A (retention time: 1.931 min, 21.26 mg, yellow oil, yield 26.58%). LCMS: 300.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ = 7.71 (d, J = 1.9Hz, 1H), 7.56-7.45 (m, 1H), 7.40 (br d, J = 8.4Hz, 1H), 7.20 (br d, J = 8.4Hz, 1H), 6.80 (s, 1H), 3.21 (br dd,J=5.4,12.1Hz,1H),3.18-3.03(m,4H),2.97-2.89(m,1H),2.76(br dd,J=5.5,8.8Hz,1H),1.97(quin,J=7.1Hz,2H),1.72-1.38(m,8H),1.36-1.25(m,2H),1.05(q,J=11.7Hz,1H).

[0428] Step 5: Synthesis of Compound 15B

[0429] Compound 15 was separated under the following conditions: column type: DAICL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode to give compound 15B (retention time: 2.445 min, 17.78 mg, yellow oil, yield 22.23%). LCMS: 300.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ = 8.57 (s, 1H), 7.81 (d, J = 2.1Hz, 1H), 7.64 (s, 1H), 7.58-7.47 (m, 1H), 7.31 (br d,J=8.1Hz,1H),6.88(d,J=1.6Hz,1H),3.98-3.53(m,5H),2.96(br dd,J=4.5,10.5Hz,1H),2.31(quin,J=7.9Hz,2H),1.80-1.31(m,10H),1.15(br d,J=11.7Hz,1H).

[0430] Example 12

[0431]

[0432] Step 1: Synthesis of compounds 16-3A-erythro and 16-3B-threo

[0433] The starting material 16-1 (500 mg, 2.46 mmol) was dissolved in tetrahydrofuran (15 mL). LiHMDS (3.0 mL, 1 M) was added at -70 °C under nitrogen protection. The reaction mixture was then reacted at -70 °C under nitrogen protection for half an hour. Then, a tetrahydrofuran solution of 16-2 (605 mg, 3.46 mmol) (5 mL) was added to the above reaction mixture, and the reaction was carried out at -70 °C under nitrogen protection for half an hour. After the reaction was completed by TLC monitoring, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (60 mL), then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give compound 16-3A-erythro (270 mg, yellow oil, yield 29.03%). 1 H NMR of 16-3A-erythro(400MHz, CDCl3-d)δ7.61(d,J=2.4Hz,1H),7.33(d,J=8.8Hz,1H),7.28(d,J=1 .6Hz,1H),7.24(d,J=8.4Hz,1H),7.15(d,J=2.0Hz,1H),6.83(dd,J1=8.0Hz,J2=1.6Hz,1H),6 .76 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.72–6.70 (m, 1H), 5.38 (d, J = 2.8 Hz, 1H), 5.28 (br.s, 1H), 3.90 (d, J = 2.4 Hz, 1H), 2.99 (s, 3H), 2.81 (s, 3H). and compound 16-3B-threo (470 mg, white solid, yield 50.54%). 1H NMR of 16-3B-threo(400MHz, CDCl3-d)δ7.62(d,J=2.4Hz,1H),7.36(d,J=8.4Hz,1H),7.32(d,J=1.6Hz,1H),7.28(d,J=2.0Hz,1H),7.15(d,J=8.0Hz,1H ), 6.89 (dd, J1 = 8.4Hz, J2 = 1.6Hz, 1H), 6.73–6.70 (m, 2H), 5.12 (d, J = 8.0Hz, 1H), 4.63 (br.s, 1H), 3.90 (d, J = 8.0Hz, 1H), 2.99 (s, 3H), 2.82 (s, 3H).

[0434] Step 2: Synthesis of compound 16-A-erythro

[0435] Compound 16-3A-erythro (160 mg, 0.38 mmol) was dissolved in tetrahydrofuran (4 mL), and lithium aluminum hydride (2.5 M, 0.59 mL) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for half an hour. After the reaction was completed as monitored by LCMS, 4 mL of tetrahydrofuran was added to dilute the reaction solution. Then, under ice bath conditions, 0.06 mL of water, 0.06 mL of 15% sodium hydroxide aqueous solution, 0.18 mL of water, and anhydrous sodium sulfate were slowly added dropwise to the reaction solution in sequence. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 18-48% acetonitrile) to obtain compound 16-A-erythro (30 mg, colorless oil, yield 19.0%). 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=2.0Hz,1H),7.41(d,J=8.0Hz,1H),7.36–7.34(m,2H),7.23(d,J=1.6Hz,1H),7.06(dd,J1=8.4Hz,J2=2.0Hz,1H), 6.97(dd,J1=8.4Hz,J2=1.6Hz,1H),6.86–6.84(m,1H),4.98(d,J=4.0Hz,1 H),3.18–3.12(m,2H),2.74–2.69(m,1H),2.58-2.53(m,1H),2.16(s,6H).

[0436] Step 3: Synthesis of compound 16-B-threo

[0437] Compound 16-3B-threo (320 mg, 0.85 mmol) was dissolved in tetrahydrofuran (8 mL), and lithium aluminum hydride (2.5 M, 1.18 mL) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for half an hour. After the reaction was completed as monitored by LCMS, 5 mL of tetrahydrofuran was added to dilute the reaction solution. Then, under ice bath conditions, 0.1 mL of water, 0.1 mL of 15% sodium hydroxide aqueous solution, 0.3 mL of water, and anhydrous sodium sulfate were slowly added dropwise to the reaction solution in sequence. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 18-48% acetonitrile) to obtain compound 16-B-threo (60 mg, colorless oil, yield 19.4%). 1 H NMR(400MHz, DMSO-d6)δ7.90(d,J=2.4Hz,1H),7.40–7.32(m,4H),7.04-6.97(m,2H),6.84(d,J=1.6H z,1H),4.88(d,J=8.4Hz,1H),3.26–3.21(m,1H),3.08–3.02(m,1H),2.69–2.64(m,1H),2.27(s,6H).

[0438] Step 4: Synthesis of compounds 16-B-1 and 16-B-2

[0439] Compound 16-B-threo (25 mg, 129.2 μmol) was separated by SFC (column type: DAICL CHIRALPAKIC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode) to give compound 16-B-1 (retention time: 1.358 min, 12.02 mg, yellow solid, yield 54.2%). LCMS: 364.2 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.89 (d, J = 2.4Hz, 1H), 7.39–7.31 (m, 4H), 7.02–6.97 (m, 2H), 6.87–6.82 (m, 1H), 4.90 (d, J = 8.0Hz, 1H), 3.22–3.17 (m, 1H), 2.99–2.93 (m, 1H), 2.57–2.54 (m, 1H), 2.21 (s, 6H). And compound 16-B-2 (retention time: 1.579 min, 8.22 mg, yellow solid, yield 36.8%). 1H NMR(400MHz, DMSO-d6)δ7.89(d,J=2.4Hz,1H),7.39–7.31(m,4H),7.02-6.97(m,2H),6.92–6.87(m,1H),6.8 4-6.83(m,1H),4.90(d,J=8.0Hz,1H),3.22–3.17(m,1H),2.98–2.93(m,1H),2.57–2.54(m,1H),2.21(s,6H).

[0440] Compounds 34B(threo), 37A(erythro), 37B(threo), 44A(erythro), 44B(threo), 45B(threo), 55B(threo), 60A(erythro), 60B(threo), 63A(erythro), 63B(threo), 72A(erythro), 72B(threo), 73A(erythro), and 73B(threo) were obtained using the same synthetic method as compound 16. Characterization data for each compound are shown in the table below.

[0441]

[0442]

[0443]

[0444] Example 13

[0445]

[0446] Step 1: Synthesis of compound 21-2

[0447] Raw material 21-1 (5.9 g, 33.49 mmol, 1 eq) was dissolved in anhydrous dichloromethane (60 mL). Under nitrogen protection, thionyl chloride (11.95 g, 100.47 mmol, 7.30 mL, 3 eq) was added at 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 5 hours. Then, anhydrous methanol (180 mL) was slowly poured into the reaction solution. After the addition was complete, the reaction solution was stirred at 20 °C for 0.1 hours. After the reaction was completed by TLC, the reaction solution was directly evaporated to dryness. After evaporation, the crude product was dissolved in ethyl acetate and neutralized with a small amount of ammonia water. Silica gel powder was then added and mixed. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 21-2 (7.3 g, yellow oil).

[0448] Step 2: Synthesis of compound 21-3

[0449] The starting material 21-2 (5.18 g, 27.24 mmol) and 4-acetaminobenzenesulfonyl azide (7.85 g, 32.68 mmol) were dissolved in acetonitrile (50 mL). Under nitrogen protection, DBU (6.16 mL, 40.85 mmol) was added at 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 16 hours. After the reaction was monitored by TLC (PE:EA = 20:1, UV 254), the reaction solution was slowly poured into water (100 mL), and then 70 mL of ethyl acetate was added for extraction three times. The combined organic phases were washed twice with 150 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 1:0-5:1) to obtain intermediate 21-3 (3.5 g, yield: 58%, red solid). 1 H NMR(400MHz,CHLOROFORM-d)δppm 7.78(s,1H),7.64(s,1H),7.64–7.52(m,1H),7.36–7.34(m,1H),6.77(s,1H),3.89(s,3H).

[0450] Step 3: Synthesis of Compounds 21-5

[0451] Starting material 21-4 (1.33 g, 5.55 mmol, 1.5 eq) and rhodium acetate dimer (81.78 mg, 185.02 μmol, 0.05 eq) were dissolved in dichloromethane (5 mL). Under nitrogen protection, a dichloromethane (5 mL) solution of starting material 21-3 (800.00 mg, 3.70 mmol, 1 eq) was added dropwise at 20 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 16 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1:0-5:1) to obtain intermediate 21-5 (450 mg, yield: 28.37%, yellow oil). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.60-7.56 (m, 2H), 7.42-7.40 (m, 1H), 7.28-7.25 (m, 1H), 6.72 (dd, J = 0.8, 2.1Hz,1H),3.69-3.53(m,3H),1.81-1.68(m,6H),1.32-1.21(m,6H),0.96-0.89(m,3H),0.72(s,7H),0.24 -0.05(m,4H),-1.13(s,2H).

[0452] Step 4: Synthesis of compounds 21-6

[0453] A solution of methyl magnesium bromide in tetrahydrofuran (1.87 mL, 5.61 mmol, 3 N) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, a solution of dimethylamine tetrahydrofuran (5.61 mL, 5.61 mmol, 1 N) was added dropwise at 0 °C. After 10 minutes, 21-5 (400 mg, 933.19 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the reaction solution at 0 °C. After the addition was complete, the mixture was stirred at 20 °C for 3 hours. After the reaction was monitored by LCMS, the reaction solution was slowly poured into an ammonium chloride aqueous solution (30 mL), and then extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed twice with 50 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 1:0-5:1) to obtain intermediate 21-6 (220 mg, yield: 53.38%, yellow oil).

[0454] Step 5: Synthesis of compounds 21-7

[0455] The raw material 21-6 (50 mg, 339.61 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, lithium aluminum hydride (2.5 M, 407.54 μL, 3 eq) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 50 °C for 1 hour. After the reaction was monitored by LCMS, water (0.1 mL), 15% sodium hydroxide aqueous solution (0.1 mL), and water (0.3 mL) were added sequentially at 0 °C to quench the reaction. Then, 5 g of anhydrous sodium sulfate was added, and the mixture was stirred for 5 minutes. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 10-50% acetonitrile) to obtain 21-7 (30 mg, yield 20.65%, pale yellow oil).

[0456] Step 6: Synthesis of Compound 21

[0457] The starting material 21-7 (30 mg, 70.14 μmol, 1 eq) was dissolved in a tetrahydrofuran solution of TBAF (1 M, 2 mL, 28.5 eq), and stirred at 20 °C for 1 hour under nitrogen protection. After the reaction was completed as monitored by LCMS, 10 mL of saturated ammonium chloride aqueous solution was added sequentially at room temperature, followed by extraction three times with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of water and 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 10-43% acetonitrile) to give compound 21 (5 mg, yield 22.46%, yellow oil). LCMS: 314.1 [M+H] + . 1HNMR (400MHz, METHANOL-d4) δ = 8.55 (s, 0.06H), 7.70 (d, J = 2.0Hz, 1H), 7.48 (d, J = 1.6Hz, 1H), 7.41 (d, J = 8.4Hz, 1H), 7.18 (dd, J = 8.4, 1.6Hz, 1H), 6 .79-6.78(m,1H),3.53-3.46(m,1H),2.90-2.74(m,1H),2.59-2.55(m,2H ),2.38-2.27(m,1H),2.23(s,6H),1.76-1.59(m,5H),1.29-1.00(m,5H).

[0458] Example 14

[0459]

[0460] Step 1: Synthesis of compound 22-2

[0461] The raw materials 22-1 (15 g, 124.85 mmol), triethylamine (21.72 mL, 156.06 mmol), and tert-butyldimethylchlorosilane (19.20 mL, 156.06 mmol) were dissolved in acetonitrile (150 mL). Under nitrogen protection, sodium iodide (23.39 g, 156.06 mmol) was added at 20 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 14 hours. After the reaction was monitored by TLC (PE:EA = 20:1, UV 254), the reaction solution was slowly poured into ice water (100 mL), and then 100 mL of ice-cold pentane was added for extraction three times. The combined organic phases were washed twice with 150 mL of 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 (silica gel column, petroleum ether / triethylamine = 1000 mL: 5 mL) to obtain intermediate 22-2 (29 g, colorless solution).

[0462] Step 2: Synthesis of compound 22-4

[0463] Starting material 22-2 (4.88 g, 20.81 mmol) and rhodium acetate dimer (0.61 g, 1.38 mmol) were dissolved in dichloromethane (30 mL). Under nitrogen protection, a dichloromethane (10 mL) solution of starting material 22-3 (3 g, 13.88 mmol) was added dropwise at 20 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 3 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was slowly poured into ice water (50 mL), and then extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed twice with 100 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 1:0-5:1) to obtain intermediate 22-4 (5.179 g, yield: 82%, pale yellow oil).

[0464] Step 3: Synthesis of compound 22-5

[0465] A methyl magnesium bromide solution (3M, 15.78 mL, 47.3 mmol) was dissolved in 20 mL of tetrahydrofuran. Under nitrogen protection, a dimethylamine methanol solution (2M, 23.66 mL, 47.3 mmol) was added dropwise at 0 °C. After ten minutes, 22-4 (2 g, 4.73 mmol) was dissolved in 5 mL of tetrahydrofuran and added dropwise to the reaction mixture at 0 °C. After the addition was complete, the mixture was stirred at 20 °C for 3 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was slowly poured into an ammonium chloride aqueous solution (100 mL), and then 100 mL of ethyl acetate was added for extraction three times. The combined organic phases were washed twice with 100 mL of 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 (silica gel column, petroleum ether / ethyl acetate = 1:0-5:1) for 22-5 (730 mg, yield: 35%, white solid).

[0466] Step 4: Synthesis of Compounds 22-6

[0467] The raw material 22-5 (600 mg, 1.38 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, lithium aluminum hydride (2.5 M, 1.65 mL, 4.13 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 50 °C for 1 hour. After the reaction was monitored by LCMS, 1 mL of water, 1 mL of 15% sodium hydroxide aqueous solution, and 3 mL of water were added sequentially at 0 °C to quench the reaction. Then, 5 g of anhydrous sodium sulfate was added, and the mixture was stirred for 5 minutes. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 10-50% acetonitrile) to obtain 22-6 (100 mg, yield 16%, pale yellow oil).

[0468] Step 5: Synthesis of Compound 22

[0469] The starting material 22-6 (100 mg, 0.237 mmol) was dissolved in tetrahydrofuran (0.5 mL). Under nitrogen protection, TBAF (1 M, 2 mL, 2 mmol) was added at 0 °C. After the addition was complete, the mixture was stirred at 50 °C for 2 hours. After the reaction was monitored by LCMS, 10 mL of water was added sequentially at room temperature, followed by 10 mL of ethyl acetate extraction three times. The combined organic phases were washed with 10 mL of water and 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (0.1% formic acid system and 10-43% acetonitrile) to give compound 22 (19 mg, yield 23%, white solid).

[0470] Step 6: Synthesis of compounds 22-A and 22-B

[0471] Compound 22 was separated and concentrated by SFC, followed by purification by reversed-phase chromatography (0.1% formic acid system and 10-43% acetonitrile) to give compound 22-A (retention time: 1.645 min, 3.46 mg, yield 18%, white solid). LCMS: 308.1 [M+H] + . 1 HNMR (400MHz, CHLOROFORM-d) δ = 8.36 (s, 0.42H, FA), 7.91 (d, J = 7.6Hz, 2H), 7.60 (d, J = 2.0Hz, 1H), 7.53 (m, 2H), 7.47-7.40 (m, 3H), 7.23 (dd, J = 8. 4,1.2Hz,1H),6.72(d,J=1.2Hz,1H),3.89-3.73(m,1H),3.62-3.48(m,1H ),3.37-3.32(m,1H),2.93-2.90(m,1H),2.79-2.74(m,1H),2.37(s,6H). Compound 22-B (retention time: 1.918 min, 5.54 mg, yield 28%, white solid). LCMS: 308.1 [M+H] + . 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.91 (d, J = 7.6Hz, 2H), 7.63-7.49 (m, 3H), 7.47-7.39 (m, 3H), 7.22 (d, J = 8.0Hz, 1H), 6.7 2(s,1H),3.89-3.76(m,1H),3.56-3.51(m,1H),3.34-3.30(m,1H),2.87-2.81(m,1H),2.71-2.66(m,1H),2.33(s,6H).

[0472] Example 15

[0473]

[0474] Step 1: Synthesis of Compound 27-2

[0475] The starting material 27-1 (6 g, 24.48 mmol, 1 eq) was dissolved in methanol (100 mL). Then, concentrated sulfuric acid (120.06 mg, 1.22 mmol, 65.25 μL, 0.05 eq) was slowly added dropwise to the mixture. The reaction mixture was stirred at 60 °C for 0.5 h. After the reaction was complete as determined by LCMS, sodium bicarbonate (300 mg) was added to the reaction mixture, and then the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give intermediate 27-2 (5 g, colorless oil, yield 78.82%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.20 (d, J = 8.4Hz, 1H), 7.14 (d, J = 2.4Hz, 1H), 6.84 (dd, J = 8.6, 2.6Hz, 1H), 3.80 (s, 3H), 3.74 (s, 2H), 3.72 (s, 3H).

[0476] Step 2: Synthesis of compound 27-4

[0477] Intermediate 27-2 (2 g, 7.72 mmol, 1 eq) and potassium fluoroborate 27-3 (2.64 g, 9.26 mmol, 1.2 eq) were dissolved in toluene (80 mL) and water (16 mL). Then, cesium carbonate (7.55 g, 23.16 mmol, 3 eq) and CATACXIUM Pd G4 (286.88 mg, 385.96 μmol, 0.05 eq) were added to the mixture under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete as determined by LCMS, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give intermediate 27-4 (900 mg, yellow oil, yield 32.62%). LCMS: 358.1 [M+H] + .

[0478] Step 3: Synthesis of compound 27-5

[0479] Intermediate 27-4 (800 mg, 2.24 mmol, 1 eq) was dissolved in methanol (20 mL). Wet palladium on carbon (119.10 mg, 111.92 μmol, 10% purity, 0.05 eq) was added to the mixture under nitrogen protection. The reaction mixture was purged three times with hydrogen and stirred for 3 hours at 20°C in a hydrogen balloon atmosphere (15 Psi). After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure to obtain crude intermediate 27-5 (499 mg, yellow oil, yield 99.85%). LCMS: 224.0 [M+H] + .

[0480] Step 4: Synthesis of compound 27-6

[0481] Intermediate 27-5 (400 mg, 1.79 mmol, 1 eq) was dissolved in anhydrous methanol (20 mL), and the reaction mixture was stirred at 60 °C for 48 hours. After the reaction was completed as determined by LCMS, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, 0.1 FA%) to give intermediate 27-6 (310 mg, white solid, yield 90.49%). 1 H NMR (400MHz, DMSO-d6) δ = 7.55 (m, 1H), 7.03-7.01 (m, 1H), 6.70-6.68 (m, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 3.45-3.39 (m, 2H), 3.00-2.92 (m, 2H).

[0482] Step 5: Synthesis of Compounds 27-7

[0483] Intermediate 27-6 (250 mg, 1.31 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL). Sodium hydroxide (104.58 mg, 2.61 mmol, 60% purity, 2 eq) was added to the mixture under nitrogen protection at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. Then, iodomethane (371.13 mg, 2.61 mmol, 162.77 μL, 2 eq) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 1 h. After the reaction was confirmed by LCMS, the reaction mixture was quenched at 0 °C with saturated ammonium chloride aqueous solution (10 mL), and then washed with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, 0.1 FA%) to obtain intermediate 27-7 (260 mg, yellow solid, yield 96.89%). 1H NMR (400MHz, DMSO-d6) δ = 7.02 (d, J = 8.4Hz, 1H), 6.73-6.63 (m, 2H), 3.74 (s, 2H), 3.72-3.67 (m, 5H), 3.09-2.96 (m, 2H), 2.87 (s, 3H).

[0484] Step 6: Synthesis of compounds 27-8

[0485] Intermediate 27-7 (260 mg, 1.27 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL). The solution was then purged three times with nitrogen and cooled to -70 °C. LiHMDS (1 M, 1.52 mL, 1.2 eq) was slowly added dropwise to the mixture under a nitrogen atmosphere at -70 °C. The reaction mixture was stirred at -70 °C for 0.5 h. Then, a tetrahydrofuran solution of cyclohexanone (186.48 mg, 1.90 mmol, 196.92 μL, 1.5 eq) was added to the reaction mixture at -0 °C. The reaction mixture was stirred at -70 °C for 0.5 h. After the reaction was complete as determined by LC-MS, the reaction mixture was quenched with hydrochloric acid (3 mL, 1 N) at -70 °C, allowed to rise naturally to room temperature, and then extracted with ethyl acetate (10 mL × 6). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, 0.1% FA) to give intermediate 27-8 (150 mg, white solid, yield 39.03%). LCMS: 286.2 [M-OH] + .

[0486] Step 7: Synthesis of Compound 27

[0487] Intermediate 27-8 (80 mg, 263.68 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (2 mL). Under nitrogen protection, a borane tetrahydrofuran complex (1 M, 1.32 mL, 5 eq) was slowly added dropwise to the mixture at 0 °C. The reaction mixture was stirred at 20 °C for 3 hours. After the reaction was completed as detected by LCMS, methanol (10 mL) was added dropwise to quench the reaction mixture at 0 °C. Then, a hydrochloric acid methanol solution (20 mL, 1 N) was added and stirred at 20 °C for 1 hour to decomplex the complex. The mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, 0.1% FA). The pH of the reversed-phase eluent was adjusted to 10 by adding potassium carbonate, and the mixture was extracted with ethyl acetate (10 mL × 6). The extract was evaporated to dryness to obtain the racemic 27-8 (70 mg, yellow oil, yield 91.07%). LCMS: 290.1 ​​[M + H] + .

[0488] Step 8: Synthesis of Compound 27

[0489] Compound 27 (170 mg, 556.67 μmol) was purified by SFC chiral separation (column type: DAICL CHIRALPAK AD (250 mm × 50 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 10%, isocratic elution mode) and lyophilized to obtain compound 27-A (retention time: 1.120 min, 10 mg, white solid, yield 14.29%) and compound 27-B (retention time: 1.198 min, 10 mg, white solid, yield 14.29%).

[0490] Compound 27-A: LCMS: 290.1 ​​[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 6.96 (d, J = 8.4Hz, 1H), 6.71-6.51 (m, 2H), 6.12-5.78 (m, 1H), 3.70 (s, 3H), 3. 63-3.50(m,1H),3.47-3.38(m,1H),2.96-2.92(m,1H),2.61-2.54(m,2H),2.32-2.23(m,4H),2.10(br t,J=12.0Hz,1H),1.85-1.82(m,1H),1.69-1.55(m,1H),1.52-1.25(m,5H),1.19-0.92(m,3H).

[0491] Compound 27-B: LCMS: 290.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 6.96 (d, J = 8.4Hz, 1H), 6.73-6.46 (m, 2H), 6.09-5.88 (m, 1H), 3.70 (s, 3H), 3. 63-3.50(m,1H),3.47-3.37(m,1H),3.01-2.89(m,1H),2.61-2.54(m,2H),2.32-2.23(m,4H),2.10(br t,J=12.0Hz,1H),1.90-1.78(m,1H),1.68-1.56(m,1H),1.53-1.26(m,5H),1.18-0.92(m,3H).

[0492] Example 16

[0493]

[0494] Compound 32 was synthesized using the same method as compound 3, and then lyophilized by reversed-phase chromatography (C18 column, 0.225% formic acid system and 12-42% acetonitrile) to obtain compound 32A (colorless gel). 1 H NMR(400MHz,CHLOROFORM-d)δ8.38(s,0.5H),7.74(s,1H),7.61(d,J=2.4Hz,1H),7.49-7.43(m,1H),7.41-7.34(m,1H),6.78-6.73(m,1H), 3.31-3.22(m,2H),3.10-3.01(m,1H),2.21(s,6H),1.83-1.72(m,1H),1.71-1.51(m,5H),1.17-1.04(m,7H),0.87(s,3H).LCMS:342.2[M+H] + And compound 32B (white solid), 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.55 (s, 1H), 7.87-7.67 (m, 1H), 7.63 (d, J = 2.1Hz, 1H), 7.59-7.33 (m, 2H), 6.76 (br d,J=4.0Hz,1H),3.62-3.47(m,2H),3.36-3.24(m,1H),2.41(s,6H),2.24-2.14(m,1H),2.03-1.66(m ,4H),1.40-1.25(m,2H),1.09-1.00(m,3H),0.78-0.69(m,3H),0.00--0.10(m,3H).LCMS:342.2[M+H] + .

[0495] Example 17

[0496]

[0497] Step 1: Synthesis of Compound 35-2

[0498] Intermediate 35-1 (3.0 g, 20.53 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Under nitrogen protection, phenyl magnesium bromide (3 M, 8.21 mL) was slowly added dropwise to the mixture at -70 °C. The reaction mixture was stirred at -70 °C for 1 hour. After the reaction was complete as determined by LC-MS, the reaction mixture was quenched at 0 °C with 1 M hydrochloric acid aqueous solution (60 mL), then extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0–4 / 1) to obtain intermediate 35-2 (4.5 g, colorless oil, yield 94.04%).

[0499] Step 2 Synthesis of compound 35-3

[0500] Intermediate 35-2 (4.5 g, 20.07 mmol) was dissolved in anhydrous dichloromethane (50 mL). Dimethyl phthalate (9.36 g, 22.07 mmol) was slowly added in portions to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed as detected by LCMS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give intermediate 35-3 (3.0 g, white solid, yield 65.66%).

[0501] Step 3: Synthesis of compound 35-4

[0502] Intermediate 35-3 (570 mg, 2.56 mmol) and N,N-dimethylthioformamide (228.00 mg, 2.56 mmol) were dissolved in anhydrous tetrahydrofuran (17 mL). Under nitrogen protection, diisopropylaminolithium (2 M, 1.28 mL) was slowly added dropwise to the mixture at -70 °C. The reaction mixture was stirred at 20 °C for 2 hours. After the reaction was completed by LCMS, 1 M hydrochloric acid aqueous solution (5 mL) was added dropwise to the reaction mixture at 0 °C, diluted with water (20 mL), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain intermediate 35-4 (390 mg, yellow oil, yield 48.83%).

[0503] Step 4: Synthesis of Compound 35

[0504] Aluminum trichloride (86 mg, 644.97 μmol) was suspended in tetrahydrofuran (6 mL). Under nitrogen protection, lithium aluminum hydride (2.5 M, 712.92 μL) was slowly added dropwise to the reaction solution at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 15 minutes. Then, intermediate 35-4 (185 mg, 594.10 μmol) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction solution at 0 °C under nitrogen protection. After the addition was complete, the mixture was heated to 10 °C and stirred for 30 minutes. After the reaction was completed by LCMS monitoring, 0.07 mL of water, 0.07 mL of 15% sodium hydroxide aqueous solution, and 0.21 mL of water were added dropwise to the reaction solution at 0 °C to quench the reaction. The solution was then dried with anhydrous sodium sulfate and filtered. The filter cake was washed with dichloromethane (10 mL × 3), and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was lyophilized by reversed-phase chromatography (C18 column, 0.1% formic acid system and 20-30% acetonitrile) to give compound 35 (103.70 mg, white solid, yield 62.04%). 1 H NMR (400MHz, DMSO-d6) δ = 8.18 (s, 0.14H), 7.93 (d, J = 2.0Hz, 1H), 7.77 (d, J = 1.6Hz, 1H), 7.54-7.38 (m,4H),7.27(t,J=7.2Hz,2H),7.20-7.11(m,1H),6.91(d,J=2.0Hz,1H),3.17(s,2H),2.12(s,6H). LCMS:282.2[M+H] + .

[0505] Example 18

[0506]

[0507] Step 1: Synthesis of Compound 36-2

[0508] Starting material 36-1 (2.0 g, 9.84 mmol) was dissolved in tetrahydrofuran (40 mL), and then triphenylphosphine (5.16 g, 19.68 mmol, 2 eq) and carbon tetrabromide (6.53 g, 19.68 mmol, 2 eq) were added in portions under nitrogen protection. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 hour. After the reaction was completed by TLC monitoring, the reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-10 / 1) to obtain intermediate 36-2 (2.4 g, yield 91.64%, colorless oil).

[0509] Step 2: Synthesis of compound 36-3

[0510] Intermediate 36-a (1.4 g, 8.91 mmol) was dissolved in tetrahydrofuran (10 mL), then purged with nitrogen. The mixture was cooled to -70 °C, and bis(trimethylsilylaminolithium) (13.36 mL, 13.36 mmol, 1.5 eq) was added. The reaction mixture was heated to 0 °C and then reacted at -0 °C for 0.5 h. Next, intermediate 36-2 (2.37 g, 8.91 mmol, 1 eq) in tetrahydrofuran (10 mL) was added at -0 °C, and the reaction mixture was reacted at -0 °C for 1 h. After the reaction was confirmed to be complete by TLC, saturated ammonium chloride aqueous solution (100 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give intermediate 36-3 (1.1 g, yield 33.1%, yellow oil).

[0511] Step 3: Synthesis of compound 36-4

[0512] Intermediate 36-3 (1.1 g, 3.21 mmol, 1 eq) was dissolved in ethanol (11 mL), and then an aqueous solution of potassium hydroxide (5 M, 11 mL, 17.12 eq) was added. The mixture was stirred at 80 °C for 24 hours. After the reaction was completed by LCMS monitoring, the reaction solution was added to water (60 mL), and the pH was adjusted to 2 with 1 M HCl. The aqueous phase was then extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain intermediate 36-4 (850 mg, yield 69.35%, yellow oil).

[0513] Step 4: Synthesis of compound 36-5

[0514] Intermediate 36-4 (850 mg, 2.35 mmol, 1 eq) was dissolved in tetrahydrofuran (8 mL), and the solution was cooled to 0 °C under nitrogen protection. Then, diisopropylethylamine (1.52 g, 11.76 mmol, 5 eq) and isopropyl chloroformate (576.42 mg, 4.70 mmol, 2 eq) were added, and the reaction mixture was reacted at 0 °C for 1.5 hours. LC-MS analysis confirmed complete reaction of the starting material. After the intermediate was formed, 3,4-dichlorophenyl magnesium bromide (0.5 M, 5.64 mL, 1.2 eq) was added to the reaction mixture, and the reaction mixture was reacted at 0 °C for 1 hour. After the reaction was detected by LCMS, saturated ammonium chloride aqueous solution (60 mL) was added dropwise to the reaction solution at 0 °C. The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 36-5 (750 mg, yield 56.02%, yellow oil).

[0515] Step 5: Synthesis of compounds 36-6

[0516] Intermediate 36-5 (400 mg, 0.815 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (3 mL), purged with nitrogen, and cooled to 0 °C. Sodium borohydride (61.17 mg, 1.63 mmol, 2 eq) was then added. After the reaction was detected by LCMS, the reaction solution was added to a saturated ammonium chloride aqueous solution (60 mL). The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain intermediate 36-6 (320 mg, yield 78.35%, yellow oil).

[0517] Step 6: Synthesis of compounds 36-7

[0518] Intermediate 36-6 (320 mg, 649.83 μmol, 1 eq) was dissolved in anhydrous dichloromethane (3 mL) and purged with nitrogen. Trifluoroacetic acid (1 mL) was then added dropwise, and the mixture was stirred at 20 °C for 30 minutes after the addition was complete. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain intermediate 36-7 (300 mg, yellow oil). This was used directly in the next step.

[0519] Step 7: Synthesis of Compound 36

[0520] Intermediate 36-7 (300 mg, 592.49 μmol) was dissolved in methanol (3 mL). Sodium acetate (97.20 mg, 1.18 mmol, 2 eq) and formaldehyde (96.17 mg, 37% purity, 1.18 mmol, 2 eq) were slowly added under nitrogen protection at 20 °C. The reaction mixture was stirred at 20 °C for half an hour. Then, sodium borohydride acetate (251.14 mg, 1.18 mmol, 2 eq) was added, and the reaction mixture was stirred at 20 °C for one hour. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation (0.1% ammonium bicarbonate system) to obtain the product, which was then purified again by reverse-phase separation (0.1% formic acid system) to obtain compound 36 (26.18 mg, yield 9.63%, yellow oil). 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.91 (d, J = 2.4Hz, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.42–7. 36(m,3H),7.15(dd,J=8.4Hz,2.0Hz,1H),7.05(dd,J=8.4Hz,1.2Hz,1H),6.87(dd,J=2.4Hz, 0.8Hz,1H),4.79(d,J=6.0Hz,1H),2.89–2.84(m,1H),2.24(t,J=7.2Hz,2H),2.18(s,6H),1. 73–1.64(m,1H),1.58–1.49(m,1H),1.43–1.26(m,2H),1.11–0.93(m,2H).LCMS:406.1[M+H] + .

[0521] Example 19

[0522]

[0523] Step 1: Synthesis of compounds 18-3A-erythro and 18-3B-threo

[0524] Dissolve raw material 18-1 (400 mg, 1.97 mmol) in tetrahydrofuran (4 mL), add LiHMDS (2.95 mL, 1 M) at -70 °C under nitrogen protection, and then react the reaction solution at -70 °C under nitrogen protection for half an hour. Then add a tetrahydrofuran (2 mL) solution of raw material 18-2 (307.41 mg, 2.56 mmol) to the above reaction solution and react at -70 °C under nitrogen protection for half an hour. After the reaction was monitored by TLC, the reaction solution was quenched at -70°C with hydrochloric acid aqueous solution (5 mL, 1N), then diluted with saturated ammonium chloride aqueous solution (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried with anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 18-3A-erythro (125 mg, colorless oil, yield 19.57%). 1 H NMR (400MHz, CDCl3-d) δ = 7.59 (d, J = 2.4Hz, 1H), 7.29 (d, J = 8.8Hz, 1H), 7.25 (d, J = 1.6Hz, 1H),7.14(d,J=7.2Hz,1H),7.29(td,J1=7.2Hz,J2=1.2Hz,1H),6.87(t,J=7.2Hz,1H),6. 70 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.89–6.68 (m, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.63 (d, J = 2.8 Hz, 1H), 5.15 (br.s, 1H), 3.96 (d, J = 2.8 Hz, 1H), 3.00 (s, 3H), 2.81 (s, 3H), 2.42 (s, 3H). Intermediate 18-3B-threo (320 mg, white solid, yield 48.00%). 1 H NMR(400MHz, CDCl3-d)δ=7.60–7.57(m,2H),7.30–7.28(m,2H),7.23(d,J=7.6Hz ,1H),7.11(td,J1=7.6Hz,J2=1.2Hz,1H),6.88(d,J=7.2Hz,1H),6.84(dd,J1=8.4 Hz,J2=2.0Hz,1H),6.65(d,J=2.0Hz,1H),5.44(dd,J1=8.0Hz,J2=3.6Hz,1H),4.4 9(d,J=4.0Hz,1H),4.07(d,J=8.0Hz,1H),3.01(s,3H),2.79(s,3H),1.70(s,3H).

[0525] Step 2: Synthesis of compound 18-A-erythro

[0526] Intermediate 18-3A-erythro (125 mg, 0.38 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum hydride (2.5 M, 0.54 mL) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for half an hour. After the reaction was completed as monitored by LCMS, 3 mL of tetrahydrofuran was added to dilute the reaction solution. Then, under ice bath conditions, 0.05 mL of water, 0.05 mL of 15% sodium hydroxide aqueous solution, 0.15 mL of water, and anhydrous sodium sulfate were slowly added dropwise to the reaction solution in sequence. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% ammonium bicarbonate system and 40-70% acetonitrile) to obtain compound 18-A-erythro (30 mg, white solid, yield 24.4%). 1 H NMR (400MHz, DMSO-d6) δ=7.87(d,J=2.4Hz,1H),7.32–7.28(m,2H),7.06(d,J=7.6Hz,1H),6.99(td,J1=6.8Hz,J2=1.6Hz,1H),6.93(dd,J1=8.8Hz,J 2=1.6Hz,1H),6.89–6.82(m,3H),5.17(s,2H),3.28–3.24(m,1H),3.09–3. 04(m,1H),2.71(dd,J1=12.0Hz,J2=7.6Hz,1H),2.27(s,3H),2.13(s,6H).

[0527] Step 3: Synthesis of compound 51B (threo)

[0528] Compound 18A (erythro) (150 mg, 0.484 mmol) was dissolved in dichloromethane (3 mL), and diethylaminosulfur trifluoride (117.22 mg, 0.727 mmol, 1.5 eq) was added under nitrogen protection at 0 °C. The reaction mixture was then stirred at 20 °C for 1 hour. After the reaction was completed by TLC monitoring, the reaction mixture was quenched with a sodium bicarbonate aqueous solution (50 mL), and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by reverse phase (ammonia system), and lyophilized to obtain 51B (threo) (80 mg, yield 50.92%, white solid). 1H NMR(400MHz, DMSO-d6)δ=7.89(d,J=1.0Hz),7.44–7.43(m,1H),7.39–7.36(m,2H),7.17–7.10(m,3H),7.01–6.98(m,1H),6.84–6.83(m,1H) ,5.87(dd,J=46.8Hz,8.0Hz,1H),3.58–3.47(m,1H),3.04(t,J=11.6Hz,1H),2.70–2.66(m,1H),2.06(s,3H),2.05(s,6H).LCMS:312.2[M+H] + .

[0529] Example 20

[0530]

[0531] Step 1: Synthesis of Compound 52-2

[0532] Starting material 52-1 (2 g, 5.28 mmol) was dissolved in tetrahydrofuran (30 mL), and wet Pd / C (168 mg) was added under nitrogen protection. The reaction solution was then reacted at 20 °C under a hydrogen balloon for 1 hour. The reaction solution was filtered and concentrated to obtain crude intermediate 52-2 (1.5 g, yellow oil, yield 98.44%). Step 2: Synthesis of compound 52-3

[0533] Intermediate 52-2 (500 mg, 1.73 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (2.5 M, 3.47 mL) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for 16 hours. After the reaction was completed as monitored by LCMS, 10 mL of tetrahydrofuran was added to dilute the reaction solution. Then, under ice bath conditions, 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution, 0.3 mL of water, and anhydrous sodium sulfate were slowly added dropwise to the reaction solution in sequence. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to obtain intermediate 52-3 (400 mg, yield 83.24%, colorless oil).

[0534] Step 3: Synthesis of compound 52-4

[0535] Intermediate 52-3 (200 mg, 0.729 mmol) and triethylamine (162 mg, 1.6 mmol) were dissolved in dichloromethane (2 mL). Ethylsulfonyl chloride (113 mg, 0.875 mmol) was slowly added while maintaining the system temperature at 0 °C, and then the mixture was stirred at 25 °C for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was poured into 10 mL of water, then extracted with dichloromethane (10 mL × 3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 52-4 (300 mg, off-white gel).

[0536] Step 4: Synthesis of Compounds 52-5

[0537] Intermediate 52-4 (270 mg, 0.737 mmol, 1 eq) and potassium iodide (61 mg, 0.369 mmol) were dissolved in anhydrous dimethyl sulfoxide (3 mL), and KCN (239 mg, 3.68 mmol) was added. The mixture was then heated to 80 °C and stirred for 16 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (30 mL), and the reaction solution was extracted with ethyl acetate (90 mL, 30 mL × 3). The combined organic phases were washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 20 / 1 - 5 / 1) to obtain intermediate 52-5 (100 mg, yield 47.90%, colorless oil).

[0538] Step 5: Synthesis of compounds 52-6

[0539] Intermediate 52-5 (200 mg, 0.714 mmol) was dissolved in ethanol (10 mL), and potassium hydroxide solution (10 mL, 5 M) was slowly added dropwise. The mixture was stirred at 80 °C for 16 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated, and the pH was adjusted to 3-4 with HCl (1 M). Ethyl acetate (90 mL, 30 mL × 3) was added to extract the reaction solution. The combined organic phases were washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude intermediate 52-6 (100 mg, white viscous substance, yield 47.16%).

[0540] Step 6: Synthesis of compounds 52-7

[0541] Magnesium methyl bromide (586.13 μL, 3 M, 10 eq) was added to a dimethylamine solution (879.20 μL, 2 M, 10 eq) under nitrogen protection at 0 °C, and then stirred at 0 °C for half an hour. Next, a tetrahydrofuran solution (2 mL) of intermediate 52-6 (50 mg, 0.175 mmol) was added to the above reaction solution at 0 °C, and the reaction solution was stirred at room temperature (30 °C) for 1 hour. After the reaction was completed as monitored by LCMS, the reaction solution was added to a saturated ammonium chloride aqueous solution (10 mL), and ethyl acetate (10 mL × 3) was added to extract the reaction solution. The combined organic phases were washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase chromatography (formic acid system) to obtain intermediate 52-7 (40 mg, yield 69.05%, white solid).

[0542] Step 7: Synthesis of Compound 52

[0543] Intermediate 52-7 (30 mg, 0.091 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (2.5 M, 0.08 mL) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for half an hour. After the reaction was completed by LCMS monitoring, 2 mL of tetrahydrofuran was added to dilute the reaction solution. Then, under ice bath conditions, 0.01 mL of water, 0.01 mL of 15% sodium hydroxide aqueous solution, 0.03 mL of water, and anhydrous sodium sulfate were slowly added dropwise to the reaction solution in sequence. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 15-45% acetonitrile), and lyophilized to obtain compound 52 (7.84 mg, colorless oil, yield 23.82%). 1 H NMR of(400MHz, DMSO-d6)δ=8.22(br.s,1H),7.69(d,J=1.2Hz,1H),7.40–7.38(m,2H),7.15(dd,J1=8.4Hz,1.2Hz,1H),2.70–2.62(m,1H),2.19(d ,J=1.2Hz,3H),2.12(s,6H),2.10–2.06(m,2H),1.92-1.81(m,2H),1.6 4–1.52(m,2H),1.46–1.30(m,4H),1.23–1.00(m,4H).LCMS:316.3[M+H] + .

[0544] Example 21

[0545]

[0546] Step 1: Synthesis of Compound 53-2

[0547] The starting material 53-1 (2.0 g, 9.84 mmol) was dissolved in tetrahydrofuran (40 mL), and then triphenylphosphine (5.16 g, 19.68 mmol, 2 eq) and carbon tetrabromide (6.53 g, 19.68 mmol, 2 eq) were added in portions under nitrogen protection. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 hour. After the reaction was completed by TLC monitoring, the reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-10 / 1) to obtain intermediate 53-2 (2.4 g, yield 91.64%, colorless oil).

[0548] Step 2 Synthesis of compound 53-3

[0549] Intermediate 53-a (1.4 g, 8.91 mmol) was dissolved in tetrahydrofuran (10 mL), then purged with nitrogen. The mixture was cooled to -70 °C, and bis(trimethylsilylaminolithium) (13.36 mL, 13.36 mmol, 1.5 eq) was added. The reaction mixture was heated to 0 °C and then reacted at -0 °C for 0.5 h. Then, a tetrahydrofuran solution of intermediate 53-2 (2.37 g, 8.91 mmol, 1 eq.) was added at -0 °C, and the reaction mixture was reacted at -0 °C for 1 h. After the reaction was confirmed to be complete by TLC, the mixture was added to a saturated ammonium chloride aqueous solution (100 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give intermediate 53-3 (1.1 g, yield 33.1%, yellow oil).

[0550] Step 3: Synthesis of compound 53-4

[0551] The starting material 53-3 (1.1 g, 3.21 mmol, 1 eq) was dissolved in ethanol (11 mL), and then an aqueous solution of potassium hydroxide (5 M, 11 mL, 17.12 eq) was added. The mixture was stirred at 80 °C for 24 hours. After the reaction was completed by LCMS monitoring, the reaction solution was added to water (60 mL), and the pH was adjusted to 2 with 1 M hydrochloric acid. The aqueous phase was then extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-3 / 1) to obtain intermediate 54-4 (850 mg, yield 69.35%, yellow oil).

[0552] Step 4: Synthesis of compound 53-5

[0553] Intermediate 54-4 (850 mg, 2.35 mmol, 1 eq) was dissolved in tetrahydrofuran (8 mL), and the solution was cooled to 0 °C under nitrogen protection. Then, diisopropylethylamine (1.52 g, 11.76 mmol, 5 eq) and isopropyl chloroformate (576.42 mg, 4.70 mmol, 2 eq) were added, and the reaction was carried out at 0 °C for 1.5 hours. LC-MS analysis confirmed complete reaction of the starting material. After the intermediate was formed, 3,4-dichlorophenyl magnesium bromide (0.5 M, 5.64 mL, 1.2 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. After the reaction was detected by LCMS, the reaction solution was added to a saturated ammonium chloride aqueous solution (60 mL). The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 53-5 (750 mg, yield 56.02%, yellow oil).

[0554] Step 5: Synthesis of compounds 53-6

[0555] Intermediate 53-5 (400 mg, 0.815 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (3 mL), purged with nitrogen, and cooled to 0 °C. Sodium borohydride (61.17 mg, 1.63 mmol, 2 eq) was then added. After the reaction was detected by LCMS, the reaction solution was added to a saturated ammonium chloride aqueous solution (60 mL). The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain intermediate 53-6 (320 mg, yield 78.35%, yellow oil).

[0556] Step 6: Synthesis of compounds 53-7

[0557] Intermediate 53-6 (320 mg, 649.83 μmol, 1 eq) was dissolved in anhydrous dichloromethane (3 mL) and purged with nitrogen. Trifluoroacetic acid (1 mL) was then added dropwise, and the mixture was stirred at 20 °C for 30 minutes after the addition was complete. After the reaction was monitored by LCMS, the reaction solution was concentrated under reduced pressure to obtain intermediate 53-7 (300 mg, yellow oil). This was used directly in the next step.

[0558] Step 7: Synthesis of Compound 53

[0559] Intermediate 53-7 (300 mg, 592.49 μmol) was dissolved in methanol (3 mL). Sodium acetate (97.20 mg, 1.18 mmol, 2 eq) and formaldehyde (96.17 mg, 37% purity, 1.18 mmol, 2 eq) were slowly added under nitrogen protection at 20 °C. The reaction mixture was stirred at 20 °C for half an hour. Then, sodium borohydride acetate (251.14 mg, 1.18 mmol, 2 eq) was added, and the reaction mixture was stirred at 20 °C for one hour. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase separation (0.1% ammonium bicarbonate system) to obtain the final product, which was then purified again by reverse-phase separation (0.1% formic acid system) to obtain compound 53 (26.18 mg, yield 9.63%, yellow oil). 1 H NMR (400MHz, DMSO-d6) δ=8.24(br.s,1H),7.91(d,J=2.4Hz,1H),7.47(d,J=8.4Hz,1H),7.42– 7.36(m,3H),7.15(dd,J1=8.4Hz,2.0Hz,1H),7.05(dd,J1=8.4Hz,1.2Hz,1H),6.87(dd,J1=2.4 Hz,0.8Hz,1H),4.79(d,J=6.0Hz,1H),2.89–2.84(m,1H),2.24(t,J=7.2Hz,2H),2.18(s,6H), 1.73–1.64(m,1H),1.58–1.49(m,1H),1.43–1.26(m,2H),1.11–0.93(m,2H).LCMS:406.1[M+H] + .

[0560] Compound 59 was synthesized using the same method as compound 53. The characterization data for the compounds are shown in the table below.

[0561]

[0562] Example 22

[0563]

[0564] Step 1: Synthesis of Compound 58-2

[0565] Intermediate 58-1 (800 mg, 4.54 mmol) was dissolved in acetonitrile (15 mL). Under nitrogen protection, 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) (1.93 g, 5.45 mmol) and 4-dimethylaminopyridine (1.11 g, 9.08 mmol) were slowly added. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was completed by TLC monitoring, the reaction mixture was directly reversed to obtain intermediate 58-2 (720 mg, white solid, yield 81.66%).

[0566] Step 2: Synthesis of compound 58-3

[0567] Intermediate 58-2 (720 mg, 3.71 mmol) and dimethylamine (2.22 mL, 2 M, THF solution) were dissolved in tetrahydrofuran (8 mL). Diisopropylethylamine (3.88 mL, 22.25 mmol) and 1-butylphosphine anhydride (1.60 g, 4.45 mmol) were slowly added at 0°C, followed by stirring at 20°C for 1 hour. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated to dryness and then purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give intermediate 58-3 (620 mg, colorless oil, yield 99.35%).

[0568] Step 3: Synthesis of compounds 58-4A (erythro) and 58-4B (threo)

[0569] Intermediate 58-3 (620 mg, 2.80 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (6 mL) under nitrogen protection. The solution was cooled to -78 °C, and LiHMDS (1 M, 4.20 mL) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. The starting material, 3,4-dichlorobenzaldehyde (735.6 mg, 4.20 mmol), was dissolved in anhydrous tetrahydrofuran (3 mL) and added dropwise to the reaction mixture at -78 °C under N2 protection. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. After the reaction was monitored by LCMS, the reaction solution was quenched in a saturated ammonium chloride aqueous solution (40 mL), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to obtain intermediate 58-4A (erythro) (600 mg, yield 43.7%, colorless viscous substance) and (silica gel column, petroleum ether / ethyl acetate = 20 / 1 - 1 / 1) to obtain intermediate 58-4B (threo) (550 mg, yield 49.16%, white solid).

[0570] Step 4: Synthesis of compounds 58A (erythro) and 58B (threo)

[0571] Aluminum trichloride (67.30 mg, 0.50 mmol) was dissolved in tetrahydrofuran (2.0 mL), and lithium aluminum hydride (2.5 M, 0.605 mL) was added under nitrogen protection. The mixture was stirred at 0°C for 15 minutes. Then, intermediate 58-4A (erythro) (200 mg, 0.504 mmol) or 58-4B (threo) (200 mg, 0.504 mmol) was dissolved in tetrahydrofuran (2 mL), and the mixture was slowly added under nitrogen protection at 0°C. The mixture was stirred at 20°C for 12 hours. After LCMS monitoring revealed the presence of the target product, the reaction solution was quenched with 0.06 mL of water, 0.06 mL of 15% NaOH aqueous solution, and 0.18 mL of water, respectively. The quenched reaction solution was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase separation (column type: Waters Xbridge C18150×25mm×5μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient elution: 50%-80% B over 15.0 min). The purified product was then lyophilized to obtain compound 58A (erythro) (54.34 mg, white solid, yield 20.60%). 1 H NMR(400MHz, CDCl3)δ9.02(br.s,1H),7.62(d,J=2.4Hz,1H),7.41(d,J=8.4Hz,1H),7 .33–7.31(m,2H),7.05(d,J=8.0Hz,1H),7.01(dd,J=8.8Hz,1.6Hz,1H),6.71(dd,J=2 .0Hz, 0.8Hz, 1H), 6.64 (dd, J=8.0Hz, 1.6Hz, 1H), 5.25 (d, J=27.2Hz, 1H), 3.30 (dd, J= 38.8Hz,14.4Hz,1H),2.86(dd,J=14.8Hz,9.6Hz,1H),2.54(s,6H).LCMS:382.2[M+H] + And compound 58B(threo) (39.74 mg, white solid, yield 28.16%), 1H NMR(400MHz, CDCl3)δ9.03(br.s,1H),7.63(d,J=2.0Hz,1H),7.40–7.38(m,2H), 7.16(d,J=1.6Hz,1H),7.12(d,J=8.0Hz,1H),7.05(dd,J=8.8Hz,1.6Hz,1H),6.72 (d,J=1.6Hz,1H),6.63(dd,J=8.4Hz,2.0Hz,1H),5.22(d,J=10.8Hz,1H),3.30(d d,J=36.4Hz,14.4Hz,1H),2.86(t,J=13.2Hz,1H),2.53(s,6H).LCMS:382.2[M+H] + .

[0572] Experimental Example 1. Test on the inhibitory effect of monoamine reuptake

[0573] 1. Experimental materials: Neurotransmitter Transporter Uptake Assay Kit (Molecular devices, Cat: R8174)

[0574] Hygromycin B(Solarbio,Cat:H8080-1g)

[0575] HBSS (Gibco, Cat: 14025076)

[0576] F TC Plate(Corning,Cat:356663)

[0577] Bravo, an automated liquid handling platform from Agilent

[0578] Testing instruments: PerkinElemer EnVision

[0579] 2. Test methods:

[0580] a. HEK293 cells expressing recombinant human dopamine transporter protein, norepinephrine transporter protein, and serotonin transporter protein were stably transfected, respectively.

[0581] b. Cell lines were cultured in DMEM medium containing 10% fetal bovine serum and 0.1 mg / mL Hygromycin B at 37°C and 5% carbon dioxide concentration, and passaged at least twice. The cell suspension was diluted to 1×10⁻⁶ using culture medium. 6 Cells / mL, seeded at 20

[0582] Add μL to a 384-well cell plate.

[0583] c. The highest detectable concentration of the reference and test compounds is 10 μM, serially diluted 4-fold. Transfer 25 μL / well of the compound dilution to a 384-well cell plate using Bravo. For high control wells, add 25 μL of 0.25% dimethyl sulfoxide to assay buffer containing BSA. For low control wells, add 25 μL of 1 μM reference solution.

[0584] d. Centrifuge at 300 rpm for 15 seconds, then incubate at 37°C for 30 minutes.

[0585] e. Prepare the test reagent using 1×HBSS, add 25 μL of the test reagent to each well, and incubate at 37°C for 60 minutes.

[0586] f. Read the test plate on EnVision. Analyze the test results using XLFIT5 software.

[0587] g. Experimental Results: The inhibitory effects of the compounds of this invention on monoamine reuptake are shown in Table 1. Wherein, A represents: IC50. 50 <10nM; B represents:

[0588] 10nM≤IC 50 <100nM; C represents: 100nM≤IC 50 <1000nM; D represents: 1000nM≤IC 50 <10000nM; E represents: IC 50 >10000nM. Average inhibition level at 10μM, * represents: inhibition 0-50%; ** represents: inhibition 51-100%.

[0589] Table 1 Results of monoamine reuptake inhibition test

[0590]

[0591]

[0592] Experimental Example 2. Functional testing of compounds on S1R receptors

[0593] 1. Experimental materials: PRE-084 (MCE, Cat#HY-18100A)

[0594] BD-1047 (MCE, Cat#HY-16996A)

[0595] Plasmid pCDH-σ1R-LgBiT-P2A-signalP-SmBiT-BiP-T2A-BSD (self-built)

[0596] Lipofectamine 2000Reagent (invitrogen, Cat#2856194)

[0597] Furimazine (PBI 3939)

[0598] BioTeK Synergy H1 Multifunctional Microplate Reader

[0599] 2. Test methods:

[0600] (1) Construct the plasmid vector pCDH-σ1R-LgBiT-P2A-signalP-SmBiT-BiP-T2A-BSD.

[0601] (2) Resuscitate 293T cells and passage them stably more than twice. Seed the cell suspension at a density of 14,000 cells / well into 96-well cell plates and culture for 22 hours.

[0602] (3) Transfect the plasmid (400 ng) with Lipofectamine 2000 Reagent reagent, incubate in an incubator for 6 h, and then replace with complete culture medium.

[0603] (4) Dilute the test compound with culture medium and incubate it in a 96-well plate containing cells for 24 hours. The highest concentration was 10 μM, with a 3-fold gradient, for a total of 10 test concentrations. 5% DMSO was used as a blank control group.

[0604] (5) Add 10 μM of luminescent substrate Furimazine and incubate for 10 min. Use an enzyme-linked immunosorbent assay (ELISA) reader to read the luminescence value.

[0605] (6) Calculate the EC50 of the compound for SIR based on the RLU (-%ΔBasal) values ​​at different concentrations. 50 or IC 50 .

[0606] 3. Experimental Results: Compared with the control group, the relative fluorescence of compounds 34, 60, 72, and 73 was significantly reduced. Therefore, compounds 34, 60, 72, and 73 were identified as effective treatments.

[0607] 73 is a sigma-receptor agonist. As shown in Table 2, its EC50... 50 The ranges are 0–100 nM, 100–1000 nM, and 1000–10000 nM, respectively.

[0608] ≥10000nM.

[0609] Table 2 shows the results of the sigma-1R agonist activity test.

[0610]

[0611] 4. Experimental conclusion: Some of the compounds in this invention are sigma-1 receptor agonists.

Claims

1. The compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: in, R1 is selected from: R 1a and R 1b Each is independently selected from: H, or C 1-6 alkyl; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; R 2a Selected from: H, or OH; R 2b Selected from: H, or OH; Or R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. X 2a and X 2c One of them is selected from: NR4, N, O, or S, and the other is selected from: C(R4)2, CR4, NR4, N, O, or S. X 2b Selected from CR4 or C(R4)2; Each occurrence is independently selected from either a single bond or a double bond; The condition is when X 2a and / or X 2c When it is O or S, it is related to X. 2a and / or X 2c Connected Selected from single bonds; Each R4 is independently selected from: H, halogen, or C. 1-6 alkyl; Y2 is selected from: CR 2c 、 or N; R 2c Selected from: H, halogen, or C 1-6 alkyl; R 2d Selected from: H, halogen, or C 1-6 alkyl; R3 is selected from: R 3a Selected from: H, halogen, OH, or oxo group (=O); R 3b Selected from: C 3-10 cycloalkyl, C 6-10 Aryl, or 5-6 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl or 5-6 heteroaryl group is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R 3c Selected from: H, or OH; X 3a X 3b X 3c X 3d X 3e Each is independently selected from C(R7)2, NR7, or O; Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being C(R7)2; R 5a and R 5b Each is independently selected from H, halogen, OH, or R. 5a R 5b Together with the carbon atoms they are attached to, they form a cyclopropyl group; R6 is independently selected from: H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy; R7 is independently selected from: H, halogen, C 1-6 Alkyl, or C 1-6 Alkyl group.

2. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, characterized in that: The compound has a structure as shown in formula (IIA) or (IIB): Among them, R1, R 1a R 1b R 2a R 2b R 2c R 2d R3, R 3a R 3b R 3c R4, R 5a R 5b R6, R7, X 2a X 2b X 2c X 3a X 3b X 3c X 3d X 3e The definitions of Y2, m, and n are as described in claim 1.

3. Compounds represented by formula (IIC) or (IID), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: in, R1 is selected from: R 1a and R 1b Each is independently selected from: H, or C 1-6 alkyl; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; Y2 is selected from: CR 2c 、 or N; R 2c Selected from: H, halogen, or C 1-6 alkyl; R 2d Selected from: H, halogen, or C 1-6 alkyl; X 2a Selected from: NR 4a 、O、or S; R 4a R 4b and R 4c Each is independently selected from: H, halogen, or C. 1-6 alkyl; R 3b Selected from: C 3-10 cycloalkyl, C 6-10 Aryl, or 5-6 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl or 5-6 heteroaryl group is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups; R 5b Selected from: H, halogen, or OH; R6 is selected from: H, halogens, C 1-6 Alkyl, or C 1-6 Alkyl group.

4. The compound according to claim 3, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, characterized in that: The compound has a structure of formula (IIC-1), (IIC-2), (IID-1), or (IID-2): Among them, R1, R 1a R 1b R 2c R 2d R 3b R 4a R 4c R 5b R6, X 2a The definitions of n are as described in claim 3.

5. The compound represented by formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: in, R 1a R 1b R 1c R 1d Each is independently selected from: H, or C 1-6 alkyl; R 2a Selected from: H, C 1-6 alkoxy group, or OH group; R 2b R 2c R 2d Each is independently selected from: H, halogen, or C. 1-6 alkyl; X 3a X 3b X 3c X 3d X 3e Each is independently selected from CH2, NH, or O; Or X 3a With X 3b， X 3b With X 3c X 3c With X 3d X 3d With X 3e Any set in C forms C 3-6 Cycloalkyl groups, the rest being CH2.

6. The compound according to claim 5, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, characterized in that: The compound has a structure as shown in formula (IIIA) or (IIIB): Among them, R 1a R 1b R 1c R 1d R 2a R 2b R 2c R 2d X 3a X 3b X 3c X 3d X 3e The definition is as described in claim 11.

7. The compound according to claim 1 or 5, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein the compound has the following structure:

8. A pharmaceutical composition comprising the compound of any one of claims 1-7, a pharmaceutically acceptable salt, stereoisomer or deuterated thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound of any one of claims 1-7, its pharmaceutically acceptable salt, stereoisomer, deuterated form, or the pharmaceutical composition of claim 8 in the preparation of a medicament for the prevention, treatment, or relief of a patient’s dopamine, norepinephrine, and / or serotonin, and / or Sigma-1 receptor-mediated disease.

10. The use according to claim 9, wherein the dopamine, norepinephrine, serotonin, and / or Sigma-1 receptor-mediated diseases include: Attention deficit hyperactivity disorder (ADHD), depression, generalized anxiety disorder, pain management, fibromyalgia, neuropathic pain, schizophrenia, eating behaviors, Parkinson's disease, Alzheimer's disease, cognitive impairment, Rett syndrome, Fragile X syndrome, epilepsy, multiple sclerosis, narcolepsy, substance addiction / abuse, obesity, sleep disorders, panic disorder, bipolar disorder, dissociative disorder, post-traumatic stress disorder, obsessive-compulsive disorder, social anxiety disorder, autism, stimulant addiction / substance abuse, drug abuse tendency, nicotine abuse, tobacco abuse, cocaine abuse, alcohol addiction, sexual dysfunction, osteoporosis, menopausal symptoms, metabolic and eating disorders, amyotrophic lateral sclerosis, stroke, bone metabolism regulation, etc.

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