Monoamine transmitter reuptake inhibitor compound and preparation method therefor and use thereof

Abstract

The present invention provides a monoamine transmitter reuptake inhibitor and a preparation method therefor and a pharmaceutical composition thereof, and further relates to a use of the compound or the pharmaceutical composition in preparation of a drug for preventing or treating dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and / or sigma-1 receptor-mediated related diseases.

Description

Monoamine reuptake inhibitor compounds and methods of making and using the same

[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, Chinese application No. 202510117370.1 filed on January 24, 2025, the contents of all of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to a class of monoamine reuptake inhibitor compounds, methods of making the compounds, and uses of the compounds for treating central nervous system (CNS) diseases or disorders. BACKGROUND

[0003] Monoamine neurotransmitters, i.e. dopamine DA, norepinephrine NE and serotonin 5-HT, in the human body, the concentration change is related to the physiological homeostatic mechanism and the physiology and pathology of a variety of serious diseases. Dopaminergic pathways play an important role in the planning and initiation of motor responses, activation, transformation, response to novelty and processing of rewards. The norepinephrine system is related to concentration, arousal regulation, signal-to-noise ratio in cortical areas, state-dependent cognitive processes and cognitive preparation for emergency stimuli. The serotonin neurotransmitter system is involved in the regulation of mood, attention, appetite, sleep and other functions. For many years, the ability to inhibit its reuptake from the synaptic cleft has been used to treat a variety of diseases.

[0004] More and more preclinical and clinical evidence shows that triple reuptake inhibitors of DA, NE and 5-HT have excellent antidepressant effects. Traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), have defects such as anhedonia, sexual dysfunction, and inability to improve cognitive impairment. Triple reuptake inhibitors as a new type of antidepressant with multiple targets, have stronger specificity, faster action and fewer adverse reactions, which can make up for the deficiencies of traditional antidepressants in clinical application, and are the key research direction of new antidepressants. The marketed triple reuptake inhibitor trorilapron venlafaxine has obvious advantages compared with traditional antidepressants, and has good safety and tolerability, does not cause drowsiness, and does not affect sexual function, body weight and lipid metabolism.

[0005] The exact biological mechanism of attention deficit hyperactivity disorder (ADHD) is still unclear, and it is generally believed to be caused by damage to part of the neurotransmitter system in the brain, especially damage to the neurotransmitter systems of dopamine, norepinephrine and 5-HT. The mechanism of action of the drugs currently used for the treatment of ADHD is to enhance the signal transduction of norepinephrine and dopamine, or to enhance the signal transduction of norepinephrine alone. Centanafadine is a triple reuptake inhibitor of DA, NE and 5-HT, which is being developed for the treatment of ADHD in children, adolescents and adults. It has reached the primary endpoint in two phase III clinical trials for the treatment of ADHD in adults and two phase III clinical trials for the treatment of ADHD in adolescents and children, significantly improved the symptoms of patients, and well tolerated.

[0006] Triple reuptake inhibitors can also be used to treat chronic pain and relieve associated depression, anxiety symptoms or sleep problems. Triple reuptake inhibitors of DA, NE and 5-HT have broad clinical prospects, so it is necessary to develop more novel triple reuptake inhibitors to meet the diverse needs of clinical treatment.

[0007] In addition to the potential of the above-mentioned triple reuptake inhibitors in the treatment of various diseases, Sigma-1 receptor has gradually become a research hotspot in the treatment of nervous system diseases. Sigma-1 receptor (σ-1R or S1R) is a subtype of the Sigma family, which is a receptor protein with chaperone activity. S1R is widely distributed in the central nervous system and peripheral organs, and is mainly distributed in the hypothalamus, thalamus, striatum, cerebellum, hippocampus and the like in the brain. At the cellular level, S1R is highly enriched in the mitochondrion-associated membrane (MAM). Under normal circumstances, the binding immunoglobulin protein (Bip) located in the MAM binds to the C-terminal of S1R and inhibits its activity; when S1R is activated, it is separated from Bip and translocates from MAM to other areas to play a role. In the central nervous system, S1R plays a role in neuroprotection and promoting nerve axon regeneration by regulating mitochondrial function, participating in cellular energy metabolism, improving oxidative stress, regulating ion channels and the like. At present, S1R has shown potential in the treatment of various nervous system diseases, including but not limited to neurodegenerative diseases, pain, stroke, retinal degeneration, Alzheimer's disease and depression. Some S1R ligands have entered clinical phase II / III trials, and no drug has been approved. SUMMARY

[0008] The present invention provides a series of compounds having norepinephrine-dopamine-serotonin reuptake inhibition and / or sigma-1 receptor modulating activity, by simultaneously inhibiting the reuptake of three monoamine neurotransmitters (norepinephrine NE, dopamine DA, serotonin 5-HT), and / or modulating Sigma-1 receptor affinity activity, thereby improving central neurotransmission, and can improve nervous system disorders, treat nervous system diseases.

[0009] In one aspect of the present invention, there is provided a compound as shown in Formula (I), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0010] wherein,

[0011] R1is selected from: said R 1a and R 1b are each independently selected from: H, or C 1-6 alkyl;

[0012] R 2a and R 2b together with the carbon atom to which they are attached form a ring

[0013] X 2a and X 2c one is selected from: O, or S, the other is selected from: O, or S, CH, or CH2,

[0014] X 2b is selected from CH, or CH2;

[0015] each occurrence is independently selected from a single bond or a double bond;

[0016] provided that when X 2a and / or X 2c is O or S, to which it is attached is selected from a single bond;

[0017] R3is selected from:

[0018] R 3a is selected from: H, or OH;

[0019] R 3b is selected from: C 3-6 cycloalkyl, or C 6-10 aryl;

[0020] R 3c is selected from: H, or OH;

[0021] X 3a , X3b , X 3c , X 3d , X 3e are each independently selected from CH2, NH, or O;

[0022] or X 3a and X 3b , X 3b and X 3c , X 3c and X 3d , X 3d and X 3e form a C 3-6 cycloalkyl, and the rest are CH2.

[0023] In another aspect of the application, there is provided a compound of Formula (IA) or (IB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0024] wherein R1, R 1a , R 1b , R 2a , R 2b , R3, R 3a , R 3b , R 3c , X 2a , X 2b , X 2c , X 3a , X 3b , X 3c , X 3d , and X 3e have the same definition as in the compound of Formula (I).

[0025] In some embodiments of the application, in the compound of Formula (I), (IA), or (IB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R1is selected from: R 1a and R 1b are each independently selected from H, methyl, ethyl, n-propyl, i-propyl;

[0026] In some embodiments of the application, in the compound of Formula (I), (IA), or (IB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, the ring is selected from the other variables are as defined in the application.

[0027] In some embodiments of the application, in the compound of Formula (I), (IA), or (IB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is selected from: R3a Selected from: H, or OH; R 3b Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; other variables are as defined in this invention.

[0028] In some embodiments of the present invention, R3 is selected from the compounds represented by formula (I), (IA), or (IB), 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 One of them is selected independently from NH or O, and the rest are selected from CH2 or X. 3a X 3b X 3c X 3d X 3e All are selected from CH2; other variables are as defined in this invention.

[0029] In some embodiments of the present invention, R3 is selected from the compounds represented by formula (I), (IA), or (IB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: 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 3e Selected from CH2; other variables are as defined in this invention.

[0030] In some embodiments of the invention, the compounds represented by formula (I), (IA), or (IB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives,

[0031] R1 is selected from:

[0032] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, isopropyl;

[0033] R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0034] R3 is selected from:

[0035] R 3c is selected from: H, or OH;

[0036] X 3a , X 3b , X 3c , X 3d , X 3e is selected from each independently NH, or O, and the rest is selected from CH2; or X 3a , X 3b , X 3c , X 3d , X 3e are all selected from CH2; or X 3a and X 3b form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, X 3c , X 3d , X 3e is selected from CH2.

[0037] In some embodiments of the present application, the compound of Formula (I), (IA) or (IB), a pharmaceutically acceptable salt, stereoisomer or deuterated thereof,

[0038] R1is selected from:

[0039] R 1a and R 1b are each independently selected from: H, methyl, ethyl, n-propyl, i-propyl;

[0040] R 2a and R 2b together with the carbon atom to which they are attached form a ring said ring is selected from

[0041] R3is selected from:

[0042] R 3a is selected from: H, or OH;

[0043] R 3b is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.

[0044] In one aspect of the present application, there is provided a compound of Formula (II), a pharmaceutically acceptable salt, stereoisomer or deuterated thereof:

[0045] wherein,

[0046] R1is selected from:

[0047] R 1a and R 1b are each independently selected from the group consisting of: H, or C 1-6 alkyl;

[0048] m is selected from 0, 1, 2, or 3;

[0049] R 2a and R 2b together with the carbon atom to which they are attached form a ring

[0050] X 2a and X 2c one is selected from: NR4, N, O, or S, the other is selected from: C(R4)2, CR4, NR4, N, O, or S,

[0051] X 2b is selected from: CR4, or C(R4)2;

[0052] each occurrence is independently selected from a single bond or a double bond;

[0053] provided that when X 2a and / or X 2c is O or S, the carbon atom to which X 2a and / or X 2c is attached is selected from a single bond;

[0054] each occurrence of R4 is independently selected from: H, halogen, or C 1-6 alkyl;

[0055] Y2is selected from: CR 2c , or N;

[0056] R 2c is selected from: H, halogen, or C 1-6 alkyl;

[0057] R 2d is selected from: H, halogen, or C 1-6 alkyl;

[0058] R3is selected from:

[0059] R 3a is selected from: H, halogen, or OH;

[0060] R 3b is selected from: C 3-10 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl, said C 3-10 cycloalkyl, C6-10 aryl, or 5-6 membered heteroaryl optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6;

[0061] R 3c is selected from: H, or OH;

[0062] X 3a , X 3b , X 3c , X 3d , X 3e each independently selected from C(R7)2, NR7, or O;

[0063] or X 3a and X 3b， X 3b and X 3c , X 3c and X 3d , X 3d and X 3e form C 3-6 cycloalkyl, the rest being C(R7)2;

[0064] R 5a and R 5b each independently selected from H, halogen, or OH;

[0065] each R6 is independently selected from: H, halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0066] each R7 is independently selected from: H, halogen, C 1-6 alkyl, or C 1-6 alkoxy.

[0067] In another aspect of the application, there is provided a compound as shown in Formula (IIA) or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0068] wherein 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 , X3b , X 3c , X 3d , X 3e , Y2, and m have the same definitions as in the compound of formula (II).

[0069] In some embodiments of the application, in the compound of formula (II), (IIA), or (IIB), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R 1a and R 1b are each independently selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl; m is selected from 0, 1, 2, or 3; and other variables are as defined in the application.

[0070] In some embodiments of the application, in the compound of formula (II), (IIA), or (IIB), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof,

[0071] R 2a and R 2b together with the carbon atom to which they are attached form a ring

[0072] X 2a and X 2c are each independently selected from the group consisting of: NR4, N, O, or S, the other is selected from the group consisting of: C(R4)2, CR4, NR4, N, O, or S;

[0073] X 2b is selected from the group consisting of: CR4, or C(R4)2;

[0074] each occurrence is independently selected from a single bond or a double bond;

[0075] provided that when X 2a and / or X 2c is O or S, the bond to X 2a and / or X 2c is a single bond;

[0076] each R4, for each occurrence, is independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl;

[0077] and other variables are as defined in the application.

[0078] In some embodiments of the application, in the compound of formula (II), (IIA), or (IIB), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R 2a and R 2b together with the carbon atom to which they are attached form a ring the ring is selected from the group consisting of

[0079] each R 4a , R 4b , R 4c , each independently, is selected from: H, halogen, or C 1-6 alkyl; further preferably from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl;

[0080] the other variables are as defined herein.

[0081] In some embodiments of the application, in a compound of Formula (II), (IIA), or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R 2c is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 2d is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; the other variables are as defined herein.

[0082] In some embodiments of the application, in a compound of Formula (II), (IIA), or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is selected from: R 3a is selected from: H, halogen, or OH; R 3b is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl is optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6; R6is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; the other variables are as defined herein.

[0083] In some embodiments of the application, in a compound of Formula (II), (IIA), or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is selected from: R 3a is selected from: H, F, Cl, Br, I, or OH; R 3b is selected from:

[0084] R 6a , R 6b , R 6c , R 6d , R 6eeach independently selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; other variables are as defined herein.

[0085] In some embodiments of the application, R3in a compound of Formula (II), (IIA), or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is selected from: R 3b selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl is optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6; R6is selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; other variables are as defined herein.

[0086] In some embodiments of the application, R3in a compound of Formula (II), (IIA), or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is selected from: R 3b selected from:

[0087] R 6a , R 6b , R 6c , R 6d , R 6e each independently selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; other variables are as defined herein.

[0088] In some embodiments of the application, R3in a compound of Formula (II), (IIA), or (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, is selected from: R 3c selected from: H, or OH; X 3a , X 3b , X 3c , X 3d , X 3e any one of X 3a , X 3b , X 3c , X 3d , X 3e are all selected from C(R7)2, or X 3a , X3b 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.

[0089] 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 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.

[0090] In some embodiments of the invention, the compounds represented by formula (II), (IIA) or (IIB), their pharmaceutically acceptable salts, stereoisomers or deuterated derivatives,

[0091] R1 is selected from:

[0092] R 1a and R 1b Each is independently selected from: H, methyl, ethyl, n-propyl, isopropyl;

[0093] m is selected from 0, 1, 2, or 3;

[0094] R 2a and R 2b Together with the carbon atoms they are attached to, they form rings. The ring Selected from

[0095] 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;

[0096] Y2 is selected from: CR 2c 、 or N;

[0097] R 2c Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0098] R 2d Selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0099] R3 is selected from:

[0100] R 3c Selected from: H, or OH;

[0101] 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 Selected from C(R7)2, or X 3a With X 3b Formation of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, X 3c X 3d X 3e Selected from C(R7)2;

[0102] R 5a and R 5b Each is independently selected from H, F, Cl, Br, I, or OH;

[0103] R7 is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0104] In one aspect of the invention, compounds of formula (IIC) or (IID), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives are provided:

[0105] in,

[0106] R1 is selected from:

[0107] R 1a and R1b Each is independently selected from: H, or C 1-6 alkyl;

[0108] m is selected from 0, 1, 2, or 3;

[0109] Y2 is selected from: CR 2c 、 or N;

[0110] R 2c Selected from: H, halogen, or C 1-6 alkyl;

[0111] R 2d Selected from: H, halogen, or C 1-6 alkyl;

[0112] X 2a Selected from: NR 4a 、O、or S;

[0113] R 4a R 4b and R 4c Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0114] 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 group, or the 5-6 heteroaryl group, is optionally replaced by one or more (e.g., 1, 2, 3, 4, 5) R6 groups;

[0115] R 5b Selected from: H, halogens, OH;

[0116] R6 is selected from: H, halogens, C 1-6 Alkyl, or C 1-6 Alkyl group.

[0117] In another 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:

[0118] Among them, R1, R 1a R 1b R 2c R 2d R 3b R 4a R 4b R 4c R 5b R6, X2a Y2, and m have the same definitions as in the compounds of formula (IIC) or (IID).

[0119] In some embodiments of the application, in a compound of formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R1is selected from: R 1a and R 1b are each independently selected from: H, methyl, ethyl, n-propyl, or i-propyl; and other variables are as defined in the application.

[0120] In some embodiments of the application, in a compound of formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R 2c is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 2d is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 4a is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 4b is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 4c is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; and other variables are as defined in the application.

[0121] In some embodiments of the application, in a compound of formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R 5b is selected from: H, F, Cl, Br, I, OH; and other variables are as defined in the application.

[0122] In some embodiments of the application, in a compound of formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R 3b is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridinyl; said phenyl, or pyridinyl is optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6; R6is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; other variables are as defined in the application.

[0123] In some embodiments of the application, in a compound of Formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated version thereof, 3b selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridinyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridinyl; said phenyl, or pyridinyl is optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6; R6is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; other variables are as defined in the application.

[0124] In some embodiments of the application, in a compound of Formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated version thereof, 3b selected from:

[0125] R 6a , R 6b , R 6c , R 6d , R 6e each independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, or i-propyloxy; other variables are as defined in the application.

[0126] In some embodiments of the application, in a compound of Formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated version thereof,

[0127] R1is selected from:

[0128] R 1a and R 1b each independently selected from: H, methyl, ethyl, n-propyl, or i-propyl;

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

[0130] Y2is selected from: CR 2c , or N;

[0131] R 2c is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl;

[0132] R 2d is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl;

[0133] X 2a is selected from: NR 4a , O, or S;

[0134] R 4a , R 4b , and R 4c are each independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl;

[0135] R 3b is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl is optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6;

[0136] R 5b is selected from: H, F, Cl, Br, I, OH;

[0137] R6is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, or i-propoxy.

[0138] In some embodiments of the application, the compound of Formula (IIC), (IID), (IIC-1), (IIC-2), (IID-1), or (IID-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof,

[0139] R1is selected from:

[0140] R 1a and R 1b are each independently selected from: H, methyl, ethyl, n-propyl, or i-propyl;

[0141] m is selected from 0, 1, 2, or 3;

[0142] Y2is selected from: CR 2c , or N;

[0143] R2c selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0144] R 2d selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0145] X 2a selected from: NR 4a , O, or S;

[0146] R 4a , R 4b , and R 4c are each independently selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0147] R 3b selected from:

[0148] R 5b selected from: H, F, CI, Br, I, OH;

[0149] R 6a , R 6b , R 6c , R 6d , R 6e are each independently selected from: H, F, CI, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0150] In another aspect of the present application, there is provided a compound as shown below, a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0151] In another aspect of the present application, there is provided a compound as shown below, a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0152] In another aspect of the present application, there is provided a pharmaceutically acceptable salt of the aforementioned compounds. The compounds of the present application are capable of forming acid addition salts and / or base addition salts. The acid addition salts can be formed with inorganic acids and organic acids, said inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; said 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, and the like.

[0153] The present application provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the above-described compounds, pharmaceutically acceptable salt, stereoisomer or deuterated form thereof and a pharmaceutically acceptable carrier. The carrier, including conventional adjuvant ingredients in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants or wetting agents, etc.

[0154] The pharmaceutical composition can be prepared into various dosage forms acceptable in pharmacy, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, nasal sprays, transdermal patches, injections or various controlled-release preparations, etc. The pharmaceutical composition can be administered orally, transmucosally, rectally or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly and intrasternally). The dosage can be appropriately adjusted according to the age, gender and disease type of the patient.

[0155] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets, capsules, liquid capsules, suspensions or liquids. The pharmaceutical composition is preferably prepared in the form of dosage units containing a particular amount of active ingredient. For example, the pharmaceutical composition can be provided in the form of tablets or capsules containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. Suitable daily dosages for humans or other mammals can vary widely according to the condition of the patient and other factors, but can be determined using conventional methods.

[0156] The present application further provides a method / use of the compound, pharmaceutically acceptable salt thereof, stereoisomer thereof, or pharmaceutical composition thereof as a medicament. The compound, pharmaceutically acceptable salt thereof, stereoisomer thereof, or pharmaceutical composition thereof can be used in a method and use for preventing, treating or ameliorating the disease pathology and / or symptoms of an animal, human.

[0157] In one aspect, the compound of the present application, pharmaceutically acceptable salt thereof, stereoisomer thereof, or pharmaceutical composition thereof has significant inhibitory activity on the reuptake of at least one or more of monoamine neurotransmitters (in particular, dopamine DA, norepinephrine NE, serotonin 5-HT). Further, the compound of the present application, pharmaceutically acceptable salt thereof, stereoisomer thereof, or pharmaceutical composition thereof has significant inhibitory activity on the reuptake of dopamine DA, norepinephrine NE, serotonin 5-HT.

[0158] In another aspect, the compounds of the present application, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof have significant affinity and modulatory (e.g., agonistic or antagonistic) effects on Sigma-1 receptors (i.e., sigma-1R, or S1R). Further, the compounds of the present application, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof have significant modulatory (e.g., agonistic or antagonistic) activity on Sigma-1 receptors (i.e., sigma-1R, or S1R) and are useful in improving or facilitating neuroprotection, neurogenesis (generation of neurons), prevention, treatment, or alleviation of pain management, psychostimulant addiction / substance abuse in a patient.

[0159] In another aspect, the present application provides the use / method of any of the above- described compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof for preventing, treating, or alleviating dopamine, norepinephrine, serotonin, and / or Sigma-1 receptor-mediated related diseases in a patient.

[0160] The present application provides the use / method of any of the above-described compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof as monoamine neurotransmitter triple reuptake inhibitors and / or Sigma-1 receptor modulators for preventing, treating, or alleviating CNS disorders, CNS diseases, and / or one or more related symptoms thereof in a patient. Further, the present application provides the use / method of preventing, treating, or alleviating CNS disorders, CNS diseases, and / or one or more related symptoms thereof in a patient by administering to the subject an effective amount of a compound of the present application, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof. The dopamine, norepinephrine, serotonin, and / or Sigma-1 receptor-mediated related diseases, CNS disorders, CNS diseases, and / or one or more related symptoms thereof include, but are not limited to, attention deficit disorder / hyperactivity syndrome (ADHD), depression, generalized anxiety disorder, pain management, fibromyalgia, neuropathic pain, schizophrenia, eating behavior, Parkinson's syndrome, Alzheimer's disease, cognitive disorders, Rett syndrome, fragile X syndrome, epilepsy, multiple sclerosis, narcolepsy, drug 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 liability, nicotine abuse, tobacco abuse, cocaine abuse, alcohol addiction, sexual dysfunction, osteoporosis, menopausal symptoms, metabolic and eating disorders, spinal cord lateral sclerosis, stroke, bone metabolism regulation, and the like.

[0161] Definitions and Descriptions

[0162] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as undefined or unclear without a specific definition, but should be interpreted according to the ordinary meaning. When a trade name appears herein, it is intended to designate the corresponding commercial product or its active ingredient.

[0163] The term "pharmaceutically acceptable," as used herein, pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0164] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is within the scope of sound medical judgment, of a compound of the present application having particular substituents discovered in the present application, with a relatively nontoxic acid or base. Alkali addition salts can be prepared from the neutral forms of the compounds of the present application by contacting these compounds in pure solution or in a suitable inert solvent with a sufficient amount of the base to produce the neutral form of the compound. Examples of pharmaceutically acceptable acid addition salts include mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, and nitrates; salts with organic acids such as acetates, tartrates, citrates, benzoates, succinates, and mandelates; and salts with amino acids such as arginates, glutamates, and aspartates. Certain specific compounds of the present application contain both basic and acidic functionalities and, as such, are capable of forming either base or acid addition salts.

[0165] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, the salt is prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.

[0166] Certain compounds of the present application can possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all intended to be within the scope of the present application.

[0167] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomeric forms, (R)- and (S)-enantiomeric forms, diastereomeric forms, (D)- isomer forms, (L)-isomer forms, as well as the racemic mixtures and other mixtures of the enantiomeric or diastereomeric forms, e.g., the racemic mixtures and other mixtures of the enantiomeric or diastereomeric forms, all of which are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0168] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to give the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the desired enantiomer recovered by conventional means known in the art, such as elution from a column or fractional crystallization. Additionally, separation of the enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0169] The compounds of the application contain one or more asymmetric centers (also referred to as chiral centers), for example chiral carbons or chiral -SO- moieties. The stereochemistry of the chiral carbon centers present in the compounds of the application is generally indicated by the names of the compounds and / or chemical structures depicted herein. Compounds of the application containing one or more chiral centers can exist as racemic mixtures, diastereomeric mixtures, enantiomerically enriched mixtures, diastereomerically enriched mixtures, or as individual stereoisomers that are either enantiomerically or diastereomerically pure. When two adjacent carbon atoms each bearing a " " carbon atom are both chiral carbon atoms, each can be in the (R) or (S) single enantiomeric form or enriched in one enantiomeric form, resulting in four stereoisomers (optical isomers), namely 1R,2R-, 1S,2S-, 1R,2S-, 1S,2R-. When the substituents on the adjacent carbon atoms are on the same side in the Fischer projection, the configuration is "erythro form", i.e., 1R,2R-, 1S,2S-. When the substituents on the adjacent carbon atoms are on the opposite side in the Fischer projection, the configuration is "threo form"; i.e., 1R,2S-, 1S,2R-.

[0170] For example: in , is the "erythro form", mixtures and / or racemates of the two can be indicated by ; is the "threo form", mixtures and / or racemates of the two can be indicated by .

[0171] The term "enantiomer" means a stereoisomer which is the mirror image of the other (non-superimposable) and which behaves as an equal and opposite mirror image.

[0172] The term "geometric isomer" is used unless otherwise indicated to refer to isomers that arise due to the inability of a double bond or a single bond in a ringed carbon atom to rotate freely.

[0173] The term "diastereomer" is used unless otherwise indicated to refer to stereoisomers that have two or more chiral centers and are not mirror images of one another.

[0174] "(D)" or "(+)" means dextrorotary, "(L)" or "(-)" means levorotary, and "(DL)" or "(±)" means racemic unless otherwise indicated.

[0175] Unless otherwise indicated, a wedge-shaped solid line bond and a wedge-shaped dashed line bond indicate the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond indicate the relative configuration of a stereocenter, and a wavy line indicates a wedge-shaped solid line bond or a wedge-shaped dashed line bond or a wavy line indicates a straight solid line bond and a straight dashed line bond

[0176] The term "pharmaceutically acceptable carrier" means any formulation or carrier medium that can deliver an effective amount of an active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include, but are not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersing agents, solubilizing agents, suspending agents, and the like.

[0177] The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to achieve the intended effect without being toxic to the subject. For oral dosage forms of the present application, an "effective amount" of one active substance in a composition means the amount needed to achieve the intended effect in conjunction with another active substance in the composition. The determination of an effective amount will vary from subject to subject, depending on the age and general condition of the subject, as well as the particular active substance, and an appropriate effective amount in a given case can be determined by those skilled in the art using routine testing.

[0178] The present application is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14C. 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.

[0179] 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.

[0180] 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.

[0181] 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. It can be understood that 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).

[0182] Unless otherwise indicated, "halogen" or "halo" by itself or as part of another group means a fluorine, chlorine, bromine, or iodine atom.

[0183] Unless otherwise indicated, "alkoxy" is used to indicate an alkyl group (including a cycloalkyl or haloalkyl group) having the indicated number of carbon atoms, connected by an oxygen bridge. Typical alkoxy groups include C 1-6 alkoxy, e.g., C1, C2, C3, C4, C5, C6alkoxy, C3, C4, C5, C6cycloalkoxy, C1, C2, C3, C4, C5, C6haloalkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, s-butyloxy, t-butyloxy, n-pentyloxy, s-pentyloxy, hexyloxy, 2-ethylbutyloxy. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy.

[0184] Unless otherwise indicated, the term "cycloalkyl" is intended to include any stable cyclic or polycyclic hydrocarbon group in which any carbon atom is saturated, can be mono- or polysubstituted, and can be univalent, divalent, or multivalent. For example C 3-10 represents 3 to 10 carbon atoms, C 3-10 is 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, norbornyl, bicyclo[2.2.1]heptyl, [2.2.2]bicyclooctyl, [4.4.0]bicyclodecyl, 2,7,7-trimethylbicyclo[2.2.1]heptan-1-yl, tricyclo[3.3.1.13]decyl (adamantyl), and the like. 3,7

[0185] Unless otherwise indicated, "aryl" refers to an aromatic carbocyclic group of from 6 to 10 carbon atoms having a single ring or multiple condensed rings. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0186] ​Unless otherwise specified, "5-6 membered heteroaryl" refers to a monovalent aromatic radical of 5 to 6 ring atoms having one or more oxygen, nitrogen and sulfur heteroatoms in the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms can optionally be oxidized. The heteroaryl group can have a single ring (e.g., pyridyl or furanyl) or multiple condensed rings, provided that the point of attachment is via a heteroaryl ring atom. Single ring heteroaryl groups typically include 5- or 6-membered aromatic rings, examples of single ring heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl.

[0187] Compounds were named by hand or by software, and commercially available compounds were named using the vendor catalog name. BRIEF DESCRIPTION OF DRAWINGS

[0188] Figure 1: Horizontal distance traveled by animals in each group within 30 min after administration of compound 3A

[0189] Figure 2: Horizontal distance traveled by animals in each group within 60 min after administration of compound 3A

[0190] Figure 3: Horizontal distance traveled by animals in each group within 30 min after administration of compound 24A

[0191] Figure 4: Horizontal distance traveled by animals in each group within 60 min after administration of compound 24A DETAILED DESCRIPTION

[0192] The present application is further illustrated by the following specific examples and test examples, which in no way should be interpreted as limiting the scope of the present application.

[0193] In the following examples, the following reagent abbreviations have the following meanings. If not defined, they are meant to have their art-recognized meanings.

[0194] Example 1

[0195] Step 1 Synthesis of compound 2-2

[0196] The raw 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-diisopropyl ethylamine (5.80 g, 44.90 mmol) was added at room temperature, HATU (5.12 g, 13.47 mmol) was added in batches at 0 °C, and after the addition was completed, the reaction liquid was stirred at 25 °C for 2 hours. After the reaction was completed by mass spectrometry, the crude product was purified by reverse phase separation method (0.1% formic acid system and 80-90% acetonitrile) to obtain compound 2-2 (2 g, yellow oil, yield 86.81%).

[0197] Step 2 synthesis of compound 2-4

[0198] Compound 2-4 (1.8 g, 9.35 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) to replace nitrogen protection, and cooled to-78 °C. Lithium di (trimethylsilyl) amine (1M, 13.15 mL) was added dropwise, and after the addition was completed, it 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 liquid under N2 protection at-78 °C. After the addition was completed, it was stirred at-78 °C for 2 hours. After the reaction was completed by LCMS, the reaction liquid 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 and extracted three times. The combined organic phase was 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 = 3 / 1-1 / 1) to obtain compound 2-4 (2.6 g, yield 97.72%, white solid).

[0199] Step 3 synthesis of compound 2

[0200] Compound 2-4 (500 mg, 1.65 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) at 0 °C, lithium aluminum hydride (2.5 M, 2.31 mL) was added dropwise, after the dropwise addition was completed, the reaction liquid was stirred at 70 °C for 1 hour. After the reaction was monitored to be completed by LCMS, the reaction liquid was cooled to 0 °C, sodium sulfate decahydrate was added to the reaction liquid until no more bubbles were generated, then 50 mL of tetrahydrofuran was added, stirred at room temperature for 30 minutes, the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase separation method (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 obtained by SFC (column type: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode).

[0201] Compound 2A: LCMS: 290.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 6.99 (s, 1H), 6.92-6.87 (m, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.59 (t, J = 8.7 Hz, 2H), 3.36-3.18 (m, 3H), 2.96 (dd, J = 3.2, 12.4 Hz, 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).

[0202] Compound 2B: LCMS: 290.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 6.97 (s, 1H), 6.87 (dd, J = 1.6, 8.2 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 4.56 (t, J = 8.6 Hz, 2H), 3.32-3.16 (m, 3H), 2.93 (dd, J = 3.3, 12.4 Hz, 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).

[0203] Compound 61 was obtained by using the same synthesis method as compound 2, and the compound characterization data are as follows:

[0204] Example 2

[0205] Compound 3 was obtained using the same synthetic method as compound 2, and was resolved by SFC (column type: DAICEL CHIRALPAK IC (250 mm x 50 mm, 10 pm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode) to obtain compound 3A (retention time: 1.412 min) and compound 3B (retention time: 1.509 min).

[0206] Compound 3A: LCMS: 288.3 [M+H] + . 1 H NMR (400 MHz, CDC13) δ = 7.61 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 1.3 Hz, 1H), 7.09 (dd, J = 1.6, 8.5 Hz, 1H), 6.76 - 6.71 (m, 1H), 3.38 (t, J = 12.4 Hz, 1H), 3.11 (dd, J = 3.3, 12.3 Hz, 1H), 2.35 (s, 7H), 1.81 - 1.72 (m, 2H), 1.72 - 1.63 (m, 1H), 1.61 - 1.50 (m, 3H), 1.44 - 1.32 (m, 2H), 1.02 - 0.78 (m, 2H).

[0207] Compound 3B: LCMS: 288.3 [M+H] + . 1 H NMR (400 MHz, CDC13) δ = 7.61 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 1.3 Hz, 1H), 7.09 (dd, J = 1.6, 8.5 Hz, 1H), 6.76 - 6.71 (m, 1H), 3.38 (t, J = 12.4 Hz, 1H), 3.11 (dd, J = 3.3, 12.3 Hz, 1H), 2.35 (s, 7H), 1.81 - 1.72 (m, 2H), 1.72 - 1.63 (m, 1H), 1.61 - 1.50 (m, 3H), 1.44 - 1.32 (m, 2H), 1.02 - 0.78 (m, 2H).

[0208] Example 3

[0209] Synthesis of compound 4-2

[0210] Dissolve the starting material 4-1 (6 g, 23.1 mmol) in dichloromethane (25 mL), replace three times nitrogen, and then cool the reaction solution to -78 °C. Slowly drop boron trichloride solution (14.3 mL, 14.30 mmol) under nitrogen atmosphere. After 15 minutes of dropping, warm the reaction solution to room temperature and react for 1 hour at room temperature. After monitoring the reaction end by LCMS, add ethyl acetate (30 mL) and water (50 mL) to the reaction solution. Extract the aqueous phase with 20 mL of ethyl acetate three times, dry the combined organic phase with 10 mL of saturated brine, and then filter and concentrate under reduced pressure to obtain compound 4-2 (5 g, yield 92.61%, white solid).

[0211] Synthesis of compound 4-3 in step 2

[0212] Dissolve compound 4-1 (5 g, 28.61 mmol) and aminoacetonitrile (10.2 g, 114.44 mmol) in 1,2-dichloroethane (150 mL), then add sodium nitrite (9.63 g, 143.05 mmol) under stirring, and finally drop water (15 mL) into the reaction solution. React the mixture at 100 °C for 12 hours. After monitoring the reaction end by LCMS, add ethyl acetate (100 mL) and water (300 mL) to the reaction solution. Extract the aqueous phase with 100 mL of ethyl acetate three times, dry the combined organic phase with 80 mL of saturated brine, and then filter and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 0-5 / 1) to obtain compound 4-3 (3 g, yield 72.54%, yellow oil).

[0213] Synthesis of compound 4-4 in step 3

[0214] Dissolve compound 4-3 (3 g, 17.32 mmol) in sodium hydroxide aqueous solution (5 M, 125 mL), and stir the reaction solution at 100 °C for 12 hours. After monitoring the reaction end by TLC, add 6 M hydrochloric acid aqueous solution to the reaction solution, adjust the pH of the reaction solution to 7, and then add ethyl acetate (80 mL) to the reaction solution. Extract the aqueous phase with 40 mL of ethyl acetate three times, dry the combined organic phase with 30 mL of saturated brine, and then filter and concentrate under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 0-5 / 1) to obtain compound 4-4 (3.2 g, yield 96.12%, white solid).

[0215] Synthesis of compound 4-5 in step 4

[0216] Compound 4-4 (3.2 g, 16.65 mmol), N,N-diisopropylethylamine (8.61 g, 66.59 mmol), dimethylamine hydrochloride (2.71 g, 33.29 mmol) were dissolved in N,N-dimethylformamide (50 mL), then HATU (7.60 g, 19.98 mmol) was added portionwise, and the mixture was reacted at 25 °C for 12 hours. After the reaction was completed by LCMS monitoring, ethyl acetate (50 mL) and water (100 mL) were added to the reaction solution, the aqueous phase was extracted with 50 mL of ethyl acetate three times, and the combined organic phase was washed with 30 mL of saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 0-3 / 1) to obtain compound 4-5 (3.4 g, yield 92.20%, white solid).

[0217] Step 5 Synthesis of compound 4-6

[0218] Compound 4-5 (2 g, 9.12 mmol) was dissolved in tetrahydrofuran (80 mL), and after three nitrogen replacements, the reaction solution was cooled to -78 °C, lithium bis(trimethylsilyl)amide (2.29 g, 13.68 mmol) was slowly added dropwise under a nitrogen atmosphere, and then the mixture was reacted at this temperature for 1 hour, and then cyclohexanone (1.79 g, 18.24 mmol) was added dropwise, and the mixture was further reacted at this temperature for 1 hour. After the reaction was completed by LCMS monitoring, ethyl acetate (100 mL) and water (200 mL) were added to the reaction solution, the aqueous phase was extracted with 80 mL of ethyl acetate three times, and the combined organic phase was washed with 50 mL of saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 0-3 / 1) to obtain compound 4-6 (2.5 g, yield 86.35%, yellow solid).

[0219] Step 6 Synthesis of compound 4

[0220] Compound 4-6 (1 g, 3.15 mmol) was dissolved in tetrahydrofuran (30 mL), then the reaction temperature was reduced to 0 °C, a solution of lithium tri-t-butoxyaluminum (2.52 mL, 6.30 mmol) was slowly added, then the reaction was heated to 70 °C for 1 hour. After the reaction was monitored to be completed by LCMS, the reaction was cooled to 0 °C, sodium sulfate decahydrate solid was slowly added in batches until no more bubbles were generated in the reaction, the reaction was stirred at this temperature for half an hour, then the reaction was filtered and concentrated under reduced pressure to obtain a crude product, then 10 mL of methanol was added to purify the slurry, and compound 4 (532 mg, white solid, yield 55.65%) was obtained after filtration. Compound 4A (retention time: 1.505 min) and compound 4B (retention time: 1.686 min) were obtained by SFC (column type: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode).

[0221] Compound 4A: LCMS: 304.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J = 5.1 Hz, 1H), 7.22 (d, J = 5.5 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.92-6.79 (m, 1H), 3.37-3.26 (m, 1H), 3.05 (dd, J = 2.9, 12.4 Hz, 1H), 2.33-2.23 (m, 7H), 1.75-1.65 (m, 2H), 1.64-1.57 (m, 1H), 1.56-1.42 (m, 3H), 1.35-1.23 (m, 2H), 0.90 (dt, J = 3.8, 13.0 Hz, 1H), 0.83-0.69 (m, 1H).

[0222] Compound 4B: LCMS: 304.2 [M+H] + . 1H NMR (400 MHz, CDC13) δ = 7.79 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 5.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.93 (br s, 1H), 3.41 (t, J = 12.4 Hz, 1H), 3.13 (dd, J = 3.0, 12.4 Hz, 1H), 2.43-2.31 (m, 7H), 1.84-1.73 (m, 2H), 1.73-1.66 (m, 1H), 1.64-1.51 (m, 3H), 1.45-1.32 (m, 2H), 0.99 (dt, J = 4.0, 13.1 Hz, 1H), 0.92-0.79 (m, 1H).

[0223] Example 4

[0224] Synthesis of compound 11-2

[0225] The starting material 11-1 (2 g, 11.35 mmol), HATU (5.18 g, 13.62 mmol), DIEA (4.35 mL, 24.98 mmol) were dissolved in dimethylformamide (30 mL), dimethylamine hydrochloride (1.02 g, 12.49 mmol) was added at 0 °C under the protection of N2, after the addition was completed, the reaction liquid was stirred at 25 °C for 12 hours. After the reaction was completed by LCMS monitoring, the reaction liquid was slowly poured into water (20 mL), then extracted with 20 mL of ethyl acetate for three times, the combined organic phase was washed with 30 mL of saturated brine twice, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase separation method (0.1% formic acid system and 10-40% acetonitrile) to obtain the intermediate 11-2 (1.3 g, yield 56.3%, brown oil).

[0226] Synthesis of compound 11-4

[0227] Intermediate 11-2 (0.6 g, 2.95 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) under the protection of N2, lithium bis(trimethylsilyl)amide (1 M, 5.9 mL) was added at -70 °C, stirred at -70 °C for 1 h, then compound 11-3 (338.36 mg, 3.19 mmol) was added dropwise at -70 °C, after the addition was completed, it was stirred at -70 °C for 3 h. After the reaction was completed by LCMS monitoring, saturated aqueous ammonium chloride solution (10 mL) was added dropwise to the reaction solution, then 10 mL of ethyl acetate was extracted three times, the combined organic phase was washed with 30 mL of saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain intermediate 11-4 (300 mg, yield 32.24%, colorless oil).

[0228] Step 3 synthesis of compound 11

[0229] Intermediate 11-4 (300 mg, 969.75 μmol) was dissolved in tetrahydrofuran (4 mL) under the protection of N2, lithium aluminum hydride (2.5 M, 1.36 mL) was slowly added to the reaction solution at 0 °C, after the addition was completed, it was warmed to 70 °C and stirred for 12 h. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with 10 mL of tetrahydrofuran, 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution and 0.6 mL of water were added in turn to quench the reaction, then an appropriate amount of anhydrous sodium sulfate was added, and then filtered through diatomite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 11 (83.1 mg, yield 28.90%, off-white sticky gel). LCMS: 296.2 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.26 (m, 1H), 7.17-7.15 (m, 3H), 6.95-6.93 (m, 2H), 6.90-6.88 (m, 1H), 6.68-6.67 (m, 1H), 5.17 (d, J = 3.6 Hz, 1H), 3.67-3.65 (m, 2H), 2.89-2.83 (m, 1H), 2.63 (s, 6H).

[0230] Example 5

[0231] Step 1 synthesis of compound 12-2

[0232] Intermediate 12-2 (430 mg, 2.12 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen protection, and cooled to -78 °C. Lithium bis(trimethylsilyl)amide (1 M, 3.17 mL) was added dropwise, and the mixture was stirred at -78 °C for 30 min. 12-3 (349.59 mg, 3.17 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) and added dropwise to the reaction solution under N2protection at -78 °C. After the addition was completed, the mixture was stirred at -78 °C for 2 h. After the reaction was completed by LCMS and TLC monitoring, the reaction solution was slowly poured into water (500 mL), and the pH was adjusted to 4 with 3N hydrochloric acid aqueous solution. The mixture was extracted with 200 mL of ethyl acetate three times, and the combined organic phase was washed with 300 mL of saturated brine once, 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 = 6 / 1-5 / 1) to obtain intermediate 12-4 (263 mg, yield 38.47%, yellow solid).

[0233] Synthesis of compound 12-4 in step 2

[0234] Intermediate 12-2 (430 mg, 2.12 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen protection, and cooled to -78 °C. Lithium bis(trimethylsilyl)amide (1 M, 3.17 mL) was added dropwise, and the mixture was stirred at -78 °C for 30 min. 12-3 (349.59 mg, 3.17 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) and added dropwise to the reaction solution under N2protection at -78 °C. After the addition was completed, the mixture was stirred at -78 °C for 2 h. After the reaction was completed by LCMS and TLC monitoring, the reaction solution was slowly poured into water (500 mL), and the pH was adjusted to 4 with 3N hydrochloric acid aqueous solution. The mixture was extracted with 200 mL of ethyl acetate three times, and the combined organic phase was washed with 300 mL of saturated brine once, 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 = 6 / 1-5 / 1) to obtain intermediate 12-4 (263 mg, yield 38.47%, yellow solid).

[0235] Synthesis of compound 12 in step 3

[0236] Intermediate 12-4 (160 mg, 510.55 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and added dropwise with lithium aluminum hydride (2.5 M, 714.76 μL) at 0 °C. After the addition was completed, the reaction solution was stirred at 70 °C for 1 h. After the reaction was completed by LCMS and TLC monitoring, the reaction solution was cooled to 0 °C, and sodium sulfate decahydrate was added until the reaction solution no longer bubbled. Then 20 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 min. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain intermediate 12 (61.89 mg, colorless oil, yield 40.20%). LCMS: 300.2 [M+H] + . 1H NMR (400 MHz, METHANOL-d4) δ = 8.60 (s, 1H), 7.91-7.79 (m, 2H), 7.62 (dd, J = 3.4, 8.4 Hz, 1H), 7.57-7.44 (m, 1H), 6.97 (dd, J = 0.6, 2.1 Hz, 1H), 4.04-3.75 (m, 2H), 3.46 (dd, J = 4.4, 9.9 Hz, 1H), 3.41-3.24 (m, 1H), 2.12-1.99 (m, 1H), 1.85-1.73 (m, 1H), 1.71-1.51 (m, 1H), 1.49-1.00 (m, 5H), 0.95-0.56 (m, 1H), 0.51 -0.06 (m, 1H).

[0237] Example 6

[0238] Step 1 Synthesis of compound 10-2

[0239] Dissolve 10-1 (2 g, 11.35 mmol), HATU (5.18 g, 13.62 mmol), DIEA (4.35 mL, 24.98 mmol) in dimethylformamide (30 mL), under the protection of N2, add dimethylamine hydrochloride (1.02 g, 12.49 mmol) at 0 °C, after the addition is completed, the reaction liquid is stirred at 25 °C for 12 hours. After monitoring the reaction is completed by LCMS, slowly pour the reaction liquid into water (20 mL), then extract with 20 mL of ethyl acetate for three times, wash the combined organic phase with 30 mL of saturated brine twice, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a crude product, which is purified by reverse phase separation method (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 10-2 (1.3 g, yield 56.3%, brown oil).

[0240] Step 2 Synthesis of compound 10-4

[0241] Intermediate 10-2 (0.6 g, 2.95 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) under the protection of N2, lithium bis(trimethylsilyl)amide (1 M, 5.9 mL) was added at -70 °C, stirred at -70 °C for 1 h, then 10-3 (357.64 mg, 3.19 mmol) was added dropwise at -70 °C, after the completion of dropwise addition, stirred at -70 °C for 3 h. After the reaction was completed by LCMS monitoring, saturated aqueous ammonium chloride solution (10 mL) was added dropwise to the reaction solution, then extracted with 10 mL of ethyl acetate for three times, the combined organic phase was washed with 30 mL of saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which 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).

[0242] Synthesis of compound 41

[0243] Intermediate 10-4 (650 mg, 2.06 mmol) was dissolved in tetrahydrofuran (7 mL) under the protection of N2, lithium aluminum hydride (2.5 M, 2.89 mL) was slowly added to the reaction solution at 0 °C, after the completion of dropwise addition, the temperature was raised to 70 °C and stirred for 12 h. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with 10 mL of tetrahydrofuran, 0.3 mL of water, 0.3 mL of 15% sodium hydroxide aqueous solution and 0.9 mL of water were added dropwise in sequence to quench the reaction, then an appropriate amount of anhydrous sodium sulfate was added, followed by filtration through diatomite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 41 (332.8 mg, yield 53.45%, off-white sticky gel). LCMS: 302.3 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.57 (s, 1H), 7.71 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.45 (m, 1H), 7.33 (m, 1H), 6.75 (m, 1H), 3.75-3.67 (m, 2H), 3.29-3.27 (m, 1H), 2.74 (dd, J = 12.40, 4.80 Hz, 1H), 2.67 (s, 6H), 2.05 (m, 1H), 1.71-1.54 (m, 4H), 1.12-0.93 (m, 6H).

[0244] Compounds 42-43 were obtained by the same synthesis method as compound 41, and the characterization data of each compound are shown in the following table:

[0245] Example 7

[0246] Synthesis of compound 16-3A-erythro and 16-3B-threo

[0247] The starting material 16-1 (500 mg, 2.46 mmol) was dissolved in tetrahydrofuran (15 mL), and LiHMDS (3.0 mL, 1 M) was added under nitrogen protection at -70 °C. The reaction solution was reacted for half an hour under nitrogen protection at -70 °C, and then a tetrahydrofuran (5 mL) solution of 16-2 (605 mg, 3.46 mmol) was added to the above reaction solution and reacted for half an hour under nitrogen protection at -70 °C. After the reaction was completed by TLC monitoring, the reaction solution was quenched with saturated aqueous ammonium chloride solution (60 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then 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 / 0-1 / 1) to obtain compound 16-3A-erythro (270 mg, yellow oil, yield 29.03%). 1 H NMR of 16-3A-erythro (400 MHz, CDC13-d) δ 7.61 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.83 (dd, J1= 8.0 Hz, J2= 1.6 Hz, 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 (400 MHz, CDC13-d) δ 7.62 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.89 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 1H), 6.73 - 6.70 (m, 2H), 5.12 (d, J = 8.0 Hz, 1H), 4.63 (br. s, 1H), 3.90 (d, J = 8.0 Hz, 1H), 2.99 (s, 3H), 2.82 (s, 3H).

[0248] Synthesis of compound 16-A-erythro in step 2

[0249] Compound 16-3A-erythro (160 mg, 0.38 mmol) was dissolved in tetrahydrofuran (4 mL), lithium aluminum hydride (2.5 M, 0.59 mL) was added slowly dropwise under nitrogen protection at 0 °C, and the mixture was stirred at 20 °C for half an hour. After the reaction was completed by LCMS monitoring, the reaction solution was first diluted with 4 mL of tetrahydrofuran, and then 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 under ice bath conditions. Filtration was performed, the filtrate was collected, and the filtrate 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 18-48% acetonitrile) to obtain compound 16-A-erythro (30 mg, colorless oil, yield 19.0%). 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.36 - 7.34 (m, 2H), 7.23 (d, J = 1.6 Hz, 1H), 7.06 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.97 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 1H), 6.86 - 6.84 (m, 1H), 4.98 (d, J = 4.0 Hz, 1H), 3.18 - 3.12 (m, 2H), 2.74 - 2.69 (m, 1H), 2.58-2.53 (m, 1H), 2.16 (s, 6H).

[0250] Synthesis of compound 16-B-threo in step 3

[0251] Compound 16-3B-threo (320 mg, 0.85 mmol) was dissolved in tetrahydrofuran (8 mL), lithium aluminum hydride (2.5 M, 1.18 mL) was added slowly dropwise under nitrogen protection at 0 °C, and the mixture was stirred at 20 °C for half an hour. After monitoring the reaction end by LCMS, 5 mL of tetrahydrofuran was first added to dilute the reaction solution, and then 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 to the reaction solution in turn under ice bath conditions. Filtration was performed, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain a crude product, which 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 (400 MHz, DMSO-d6) δ 7.89 (d, J = 2.4 Hz, 1H), 7.39 - 7.31 (m, 4H), 7.02-6.97 (m, 2H), 6.87-6.82 (m, 1H), 4.90 (d, J = 8.0 Hz, 1H), 3.22-3.17 (m, 1H), 2.99-2.93 (m, 1H), 2.57-2.54 (m, 1H), 2.21 (s, 6H).

[0252] Synthesis of compound 16-B-1 and 16-B-2

[0253] Compound 16-B-threo (25 mg, 129.2 μmol) was separated by SFC (column type: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [C02-EtOH (0.1% NH3H20)]; B%: 30%, isocratic elution mode) to obtain compound 16-B-1 (retention time: 1.358 min, 12.02 mg, yellow solid, yield 54.2%). LCMS: 364.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 2.4 Hz, 1H), 7.39 - 7.31 (m, 4H), 7.02-6.97 (m, 2H), 6.87-6.82 (m, 1H), 4.90 (d, J = 8.0 Hz, 1H), 3.22-3.17 (m, 1H), 2.99-2.93 (m, 1H), 2.57-2.54 (m, 1H), 2.21 (s, 6H). 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 2.4 Hz, 1H), 7.39 - 7.31 (m, 4H), 7.02-6.97 (m, 2H), 6.92-6.87 (m, 1H), 6.84-6.83 (m, 1H), 4.90 (d, J = 8.0 Hz, 1H), 3.22-3.17 (m, 1H), 2.98-2.93 (m, 1H), 2.57-2.54 (m, 1H), 2.21 (s, 6H).

[0254] Compounds 38B-1 (threo), 38B-2 (threo), 40A (erythro), 40B (threo), 41A (erythro), 41B (threo), 54A (erythro), 54B (threo), 56A (erythro), 56B (threo) were obtained using the same synthetic procedure as compound 16. Characterization data for each compound are listed in the table below:

[0255] Example 8

[0256] Step 1 Synthesis of compound 17-3

[0257] The starting material 17-1 (2 g, 9.48 mmol, 1 eq) was dissolved in anhydrous dioxane (60 mL) and water (12 mL), cesium carbonate (9.26 g, 9.48 mmol, 3 eq), starting material 17-2 (2.03 g, 10.42 mmol, 1.1 eq), Xphos Pd G4 (815 mg, 0.95 mmol, 0.1 eq) were added, the reaction system was replaced with nitrogen gas, and then the reaction liquid was stirred at 100 °C for 16 hours. After the reaction was monitored to be completed by LCMS, the reaction liquid was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase separation method (petroleum ether / ethyl acetate = 20 / 1-5 / 1) to obtain 17-3 (770 mg, 34.6% yield).

[0258] Red-brown oil, yield 46.69%. 1 H NMR (400 MHz, CDCl3-d) δ = 7.51 (d, J = 0.8 Hz, 1H), 7.45 (dd, J1= 8.8H, J2= 3.6 Hz, 2H), 7.21 (dd, J1= 8.8H, J2= 2.0 Hz, 1H), 3.87 (s, 2H), 2.26 (s, 3H).

[0259] Step 2 Synthesis of compound 17-4

[0260] Intermediate 17-3 (770 mg, 4.5 mmol, 1 eq) was dissolved in absolute ethanol (20 mL) and a solution of KOH (5 M, 20 mL, 22.23 eq) was added. The reaction was stirred at 90 °C for 12 h. After the reaction was monitored to be completed by LCMS, the reaction was concentrated under reduced pressure to remove the ethanol in the system, and then extracted with ethyl acetate (90 mL, 30 mL x 3) for the first time. The organic phase was discarded, and the water phase was adjusted to pH < 2 with 5 N hydrochloric acid aqueous solution, and then extracted with ethyl acetate (90 mL, 30 mL x 3). The second extracted organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 17-4 (834 mg, yield 96.67%, yellow solid) which was directly used in the next reaction. 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (br. s, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.18 (d, J = 2.4 Hz, 1H), 3.65 (s, 2H), 2.19 (s, 3H).

[0261] Step 3 synthesis of compound 17-5

[0262] Intermediate 17-4 (1 g, 5.26 mmol, 1 eq) was dissolved in N,N'-dimethylformamide (15 mL), and diisopropylethylamine (4.08 g, 31.55 mmol, 5.49 mL, 6 eq) was added dropwise. After the addition was completed, the reaction was stirred at 0 °C for 3 min, and then HATU (2.4 g, 6.31 mmol, 1.2 eq) was added to the reaction in batches, and stirred for 3 min. Then a solution of dimethylamine hydrochloride (643 mg, 7.89 mmol, 1.5 eq) in N,N'-dimethylformamide (15 mL) was added dropwise to the reaction, stirred for 3 min, and then the reaction system was naturally warmed to 20 °C and stirred for 2 h. After the reaction was monitored to be completed by LCMS, the reaction was poured into ice-salt water (45 mL) and extracted with ethyl acetate (120 mL, 40 mL x 3). The combined organic phase was washed with hydrochloric acid (15 mL, 5 mL x 3), saturated sodium bicarbonate solution (10 mL), saturated brine (90 mL, 30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by normal phase chromatography (petroleum ether / ethyl acetate = 20 / 1-1 / 1) to obtain intermediate 17-5 (580 mg, orange oil, yield 50.77%). 1H NMR (400 MHz, DMSO-d6) d = 7.74 (d, J = 1.1 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.16 (dd, J = 1.6, 8.4 Hz, 1H), 3.78 (s, 2H), 3.03 (s, 3H), 2.84 (s, 3H), 2.19 (d, J = 1.1 Hz, 3H).

[0263] Synthesis of compound 17-7 in step 4

[0264] Intermediate 17-5 (560 mg, 2.58 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (12 mL) under nitrogen protection, and cooled to -78 °C. LiHMDS (1 M, 3.1 mL, 1.2 eq) was added dropwise, and after the addition was completed, the reaction was stirred at -78 °C for 30 min. The raw material 17-6 (354 mg, 3.61 mmol, 1.4 eq) was dissolved in anhydrous tetrahydrofuran (2 mL) under nitrogen protection, and added dropwise to the reaction solution at -78 °C. After the addition was completed, the reaction was stirred at -78 °C for 30 min. After the reaction was completed by LCMS monitoring, hydrochloric acid (4.6 mL, 1 N) was added slowly at -78 °C to quench the reaction, and the reaction was slowly warmed to 20 °C and stirred for 1 h. Water (20 mL) was added, and the reaction was extracted with ethyl acetate (90 mL, 30 mL x 3). The combined organic phase was washed with saturated brine (45 mL, 15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 20 / 1-5 / 1) to give intermediate 17-7 (750 mg, yield 92.06%, colorless oil). 1 H NMR (400 MHz, CDCl3-d) d = 7.57 (d, J = 1.6 Hz, 1H), 7.39 - 7.37 (m, 2H), 7.26 - 7.22 (m, 1H), 5.90 - 5.42 (m, 1H), 3.76 (s, 1H), 2.99 (s, 3H), 2.95 (s, 3H), 2.24 (s, 3H), 1.95 - 1.90 - 1.70 (m, 2H), 1.65 - 1.54 (m, 1H), 1.51 - 1.38 (m, 4H), 1.23 - 1.10 (m, 3H).

[0265] Synthesis of compounds 17-A and 17-B in step 5

[0266] Intermediate 17-7 (400 mg, 1.27 mmol) was dissolved in tetrahydrofuran (10 mL) and lithium aluminum hydride (2.5 M, 1.78 mL) was added slowly dropwise at 0 °C under nitrogen protection. The mixture was stirred at 20 °C for half an hour. After the reaction was monitored to be completed by LCMS, the reaction solution was diluted with 5 mL of tetrahydrofuran first, and then 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution, 0.6 mL of water and anhydrous sodium sulfate were added slowly dropwise to the reaction solution under ice bath condition successively. Filtration was performed, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase separation (0.1% ammonium bicarbonate system and 48-78% acetonitrile) to obtain 17, and then 17 was separated by SFC (column type: DAICEL CHIRALPAK IK (250 mm x 50 mm, 10 pm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode) to obtain compound 17-A (retention time: 1.189 min, 28.8 mg, yield 7.54%, white solid). LCMS: 302.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.70 (s, 1H), 7.39-7.35 (m, 2H), 7.17 (d, J = 8.8 Hz, 1H), 5.35 (br. s, 1H), 3.10-3.05 (m, 1H), 2.97-2.93 (m, 1H), 2.63-2.58 (m, 1H), 2.19 (s, 3H), 2.18 (s, 6H), 1.61-1.31 (m, 7H), 1.23-1.04 (m, 2H), 0.97-0.88 (m, 1H). And compound 17-B (retention time: 1.299 min, 33.63 mg, yield 8.74%, white solid). LCMS: 302.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.69 (d, J = 0.8 Hz, 1H), 7.39-7.36 (m, 2H), 7.17 (dd, J1= 8.4 Hz, J2= 1.2 Hz, 1H), 5.32 (br. s, 1H), 3.07-3.02 (m, 1H), 2.96-2.92 (m, 1H), 2.60-2.54 (m, 1H), 2.19 (d, J = 0.8 Hz, 3H), 2.15 (s, 6H), 1.61-1.50 (m, 4H), 1.45-1.31 (m, 3H), 1.23-1.04 (m, 2H), 0.96-0.87 (m, 1H).

[0267] Example 9

[0268] Step 1 Synthesis of compound 18-3A-erythro and 18-3B-threo

[0269] The starting material 18-1 (400 mg, 1.97 mmol) was dissolved in tetrahydrofuran (4 mL), and LiHMDS (2.95 mL, 1 M) was added under nitrogen protection at -70 °C. The reaction solution was reacted for half an hour under nitrogen protection at -70 °C, and then a tetrahydrofuran (2 mL) solution of the starting material 18-2 (307.41 mg, 2.56 mmol) was added to the above reaction solution and reacted for half an hour under nitrogen protection at -70 °C. After the reaction was completed by TLC monitoring, the reaction solution was quenched with hydrochloric acid aqueous solution (5 mL, 1 N) at -70 °C, diluted with saturated aqueous ammonium chloride solution (50 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (100 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 / 0-1 / 1) to obtain intermediate 18-3A-erythro (125 mg, colorless oil, yield 19.57%). 1 H NMR (400 MHz, CDC13-d) d = 7.59 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.29 (td, J1= 7.2 Hz, J2= 1.2 Hz, 1H), 6.87 (t, J = 7.2 Hz, 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%). 1H NMR (400 MHz, CDC13-d) δ = 7.60 - 7.57 (m, 2H), 7.30 - 7.28 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.11 (td, J1= 7.6 Hz, J2= 1.2 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.84 (dd, J1= 8.4 Hz, J2= 2.0 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 5.44 (dd, J1= 8.0 Hz, J2= 3.6 Hz, 1H), 4.49 (d, J = 4.0 Hz, 1H), 4.07 (d, J = 8.0 Hz, 1H), 3.01 (s, 3H), 2.79 (s, 3H), 1.70 (s, 3H).

[0270] Synthesis of compound 18-A-erythro in step 2

[0271] The 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 monitored to be completed by LCMS, the reaction solution was first diluted with 3 mL of tetrahydrofuran, and then 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 under ice bath conditions. Filtration was performed, and the filtrate was collected and concentrated under reduced pressure to obtain a 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 (400 MHz, DMSO-d6) δ = 7.87 (d, J = 2.4 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 (td, J1= 6.8 Hz, J2= 1.6 Hz, 1H), 6.93 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 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= 12.0 Hz, J2= 7.6 Hz, 1H), 2.27 (s, 3H), 2.13 (s, 6H).

[0272] Synthesis of compound 18-B-threo in step 3

[0273] Intermediate 18-3B-threo (320 mg, 0.99 mmol) was dissolved in tetrahydrofuran (5 mL), lithium aluminum hydride (2.5 M, 1.39 mL) was added slowly dropwise under nitrogen protection at 0 °C, and the mixture was stirred at 20 °C for half an hour. After monitoring the reaction end by LCMS, the reaction solution was first diluted with 5 mL of tetrahydrofuran, and then 0.13 mL of water, 0.13 mL of 15% sodium hydroxide aqueous solution, 0.4 mL of water and anhydrous sodium sulfate were slowly added to the reaction solution in turn under ice bath conditions. Filtration was performed, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase separation (0.1% ammonium bicarbonate system and 42-72% acetonitrile) to obtain compound 18-B-threo (80 mg, white solid, yield 25.6%). 1 H NMR (400 MHz, DMSO-d6) d = 7.86 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.08 (t, J = 7.6 Hz, 1H), 7.02 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 6.97 (td, J1= 7.2 Hz, J2= 1.2 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.82 - 6.80 (m, 1H), 6.56 (br. s, 2H), 5.04 (d, J = 7.6 Hz, 1H), 3.29 - 3.21 (m, 2H), 3.07 - 3.02 (m, 1H), 2.66 (dd, J1= 12.0 Hz, J2= 6.4 Hz, 1H), 2.19 (s, 6H), 2.01 (s, 3H).

[0274] Synthesis of compound 18-B-1 and 18-B-2

[0275] Intermediate 18-B-threo (40 mg, 129.2 pmol) was separated by SFC (column type: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 pm); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to obtain compound 18-B-1 (retention time: 1.507 min, 16.95 mg, yellow oil, yield 37.7%). LCMS: 310.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 7.86 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.02 (dd, Ji = 8.4 Hz, J2= 1.6 Hz, 1H), 6.97 (td, Ji = 7.2 Hz, J2= 1.2 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.82 - 6.80 (m, 1H), 5.04 (d, J = 8.0 Hz, 1H), 3.27 - 3.22 (m, 1H), 3.08 - 3.02 (m, 1H), 2.66 (dd, Ji = 12.0 Hz, J2= 6.4 Hz, 1H), 2.19 (s, 6H), 2.01 (s, 3H).

[0276] and compound 18-B-2 (retention time: 1.675, 0.14.00 mg, yellow oil, yield 30.9%). LCMS: 302.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 7.86 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.02 (dd, Ji = 8.4 Hz, J2= 1.6 Hz, 1H), 6.97 (td, Ji = 7.2 Hz, J2= 1.2 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.82 - 6.80 (m, 1H), 5.04 (d, J = 8.0 Hz, 1H), 3.27 - 3.22 (m, 1H), 3.08 - 3.02 (m, 1H), 2.66 (dd, Ji = 12.0 Hz, J2= 6.4 Hz, 1H), 2.19 (s, 6H), 2.01 (s, 3H).

[0277] Example 10

[0278] Step 1 synthesis of compound 19-3-erythro and 19-4-threo

[0279] Intermediate 19-1 (0.5 g, 2.46 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), under the protection of nitrogen, -70 °C, lithium bis(trimethylsilyl)amide (1 M, 3.69 mL) was added, stirred at -70 °C for 0.5 h, then 19-2 (435 mg, 3.2 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), added dropwise into the reaction solution at -70 °C, after the dropwise addition was completed, stirred at -70 °C for 0.5 h. After the reaction was completed by LCMS monitoring, 10 mL of saturated aqueous ammonium chloride solution was added dropwise into the reaction solution, then 50 mL of ethyl acetate was added to extract three times, the combined organic phase was washed with 30 mL of saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain intermediate 19-3-erythro (200 mg, yield 23%, colorless oil) and (silica gel column, petroleum ether / ethyl acetate = 2 / 1-1 / 1), intermediate 19-4-threo (350 mg, yield 37.73%, white solid).

[0280] Synthesis of compound 19-A-erythro

[0281] Intermediate 19-3-erythro (200 mg, 589 μmol) was dissolved in tetrahydrofuran (4 mL), under the protection of N2, 2.5 M lithium aluminum hydride (0.825 mL) was slowly added dropwise into the reaction solution at 0 °C, after the dropwise addition was completed, the temperature was increased to 20 °C and stirred for 0.5 h. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with 10 mL of tetrahydrofuran, 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution and 0.6 mL of water were added dropwise in sequence to quench the reaction, then an appropriate amount of anhydrous sodium sulfate was added, and then filtered through diatomite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 19-A-erythro (90 mg, yield 40.83%, off-white sticky gel). LCMS: 326.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 7.85 (d, J = 2.0 Hz, 1H), 7.33-7.16 (m, 2H), 7.11-6.98 (m, 1H), 6.94-6.86 (m, 2H), 6.83-6.77 (m, 2H), 6.64-6.56 (m, 1H), 5.33 (d, J = 3.2 Hz, 1H), 3.80 (s, 3H), 3.23 (dt, J = 7.6, 3.6 Hz, 2H), 2.94-2.91 (m, 1H), 2.58-2.55 (m, 1H), 2.23 (s, 6H).

[0282] Step 3 synthesis of compound 19-B-threo

[0283] Intermediate 19-4-threo (350 mg, 1.03 mmol) was dissolved in tetrahydrofuran (7 mL), under the protection of N2, lithium aluminum hydride (2.5 M, 1.44 mL) was slowly added to the reaction solution at 0 °C, after the addition was completed, the temperature was raised to 20 °C and stirred for 0.5 h. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with 10 mL of tetrahydrofuran, 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution and 0.6 mL of water were added in turn to quench the reaction, then an appropriate amount of anhydrous sodium sulfate was added, and then filtered through diatomite, and the filtrate was collected and rotary evaporated to give a crude product. The crude product was purified by reverse phase separation method (0.1% formic acid system and 10-40% acetonitrile) to give 19-B-threo (96 mg, yield 25.06%, off-white sticky glue). LCMS: 326.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.19 (0.71H, FA), 7.88 (d, J = 2.0 Hz, 1H), 7.47-7.23 (m, 3H), 7.09-7.07 (m, 2H), 6.91-6.82 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 5.15 (d, J = 6.6 Hz, 1H), 3.57 (s, 3H), 3.27-3.26 (m, 2H), 2.85-3.82 (m, 2H), 2.16 (s, 6H).

[0284] Example 11

[0285] Step 1 synthesis of compound 20-3-erythro and 20-4-threo

[0286] Intermediate 20-1 (0.5 g, 2.46 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), under the protection of nitrogen, lithium bis(trimethylsilyl)amide (1 M, 3.69 mL, 3.69 mmol) was added at -70 °C, and stirred at -70 °C for 0.5 h, then the raw material 20-2 (435 mg, 3.2 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and added dropwise into the reaction solution at -70 °C, after the dropwise addition was completed, it was stirred at -70 °C for 0.5 h. After the reaction was completed by LCMS monitoring, saturated aqueous ammonium chloride solution (10 mL) was added dropwise into the reaction solution, then 10 mL of ethyl acetate was added for extraction three times, the combined organic phase was washed with 30 mL of saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain intermediate 20-3-erythro (230 mg, yield 26.92%, colorless oil) and (silica gel column, petroleum ether / ethyl acetate = 2 / 1-1 / 1), intermediate 20-4-threo (300 mg, yield 33.70%, white solid).

[0287] Synthesis of compound 20-A-erythro

[0288] Intermediate 20-3-erythro (230 mg, 668 μmol) was dissolved in tetrahydrofuran (5 mL), under the protection of N2, lithium aluminum hydride (2.5 M, 0.535 mL) was slowly added dropwise into the reaction solution at 0 °C, after the dropwise addition was completed, it was warmed to 20 °C and stirred for 0.5 h. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with 10 mL of tetrahydrofuran, 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution and 0.6 mL of water were added dropwise in sequence to quench the reaction, then an appropriate amount of anhydrous sodium sulfate was added, and then filtered through diatomite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 20-A-erythro (92 mg, yield 41.40%, off-white sticky gel). LCMS: 330.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 0.77H, FA), 7.89 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.24-7.05 (m, 3H), 6.85 (d, J = 1.2 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 3.34-3.32 (m, 1H), 2.98-2.77 (m, 3H), 2.15 (s, 6H).

[0289] Synthesis of compound 20-B-threo

[0290] Intermediate 20-4-threo (300 mg, 0.872 mmol) was dissolved in tetrahydrofuran (6 mL), under the protection of nitrogen, lithium aluminum hydride (2.5 M, 0.698 mL) was slowly added to the reaction solution at 0 °C, after the addition was completed, the temperature was raised to 20 °C and stirred for 0.5 h. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with 10 mL of tetrahydrofuran, 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution and 0.6 mL of water were added in turn to quench the reaction, then an appropriate amount of anhydrous sodium sulfate was added, and then filtered through diatomite, and the filtrate was collected and rotary evaporated to obtain the crude product. The crude product was purified by reverse phase separation method (0.1% formic acid system and 10-40% acetonitrile), and then purified by SFC separation, and then purified by reverse phase separation method (0.1% formic acid system and 10-40% acetonitrile) to obtain compound 20-B-threo (2.72 mg, yield 0.829%, off-white sticky glue). LCMS: 330.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 0.77H, FA), 7.89 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.24-7.05 (m, 3H), 6.85 (d, J = 1.2 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 3.34-3.32 (m, 1H), 2.98-2.77 (m, 3H), 2.15 (s, 6H).

[0291] Example 12

[0292] Synthesis of compound 23-3-erythro and 23-4-threo

[0293] Intermediate 23-1 (500 mg, 2.46 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), under the protection of nitrogen, lithium bis(trimethylsilyl)amide (1 M, 3 mL) was slowly added dropwise to the mixture at -70 °C, and the reaction was stirred at -70 °C for 0.5 h. Then the raw material 23-2 (605.00 mg, 3.46 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), which was slowly added dropwise to the reaction at -70 °C, and stirred at -70 °C for 0.5 h. After the reaction was detected by LCMS, 1 M aqueous hydrochloric acid (4 mL) was added dropwise to quench the reaction at 0 °C, diluted with water (20 mL), and then extracted with ethyl acetate (20 mL x 3), the organic phase was washed with brine (20 mL), then 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 = 10 / 1 ~ 2 / 1) to obtain intermediate 23-3-erythro (305 mg, white solid, yield 32.78%) and intermediate 23-4-threo (337 mg, white solid, yield 36.21%).

[0294] Synthesis of compound 23-A-erythro

[0295] Intermediate 23-3-erythro (305.00 mg, 806.35 μmol) was dissolved in tetrahydrofuran (10 mL), under the protection of nitrogen, lithium aluminum hydride (2.5 M, 1.13 mL) was slowly added dropwise to the reaction at 0 °C, and then the temperature was raised to 20 °C and stirred for 40 min. After the reaction was detected by LCMS, 0.11 mL of water, 0.11 mL of 15% aqueous sodium hydroxide solution and 0.33 mL of water were added dropwise to quench the reaction at 0 °C, then dried over anhydrous sodium sulfate, filtered, the filter cake was washed with ethyl acetate (15 mL x 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was freeze-dried by reversed-phase chromatography column (C 18 18 column, 0.1% formic acid system and 12-42% acetonitrile) to obtain compound 23-A-erythro (106.39 mg, off-white solid, yield 36.11%). LCMS: 308.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 8.16 (s, 0.7H), 7.87 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 6.90 - 6.82 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 5.36 (d, J = 3.2 Hz, 1H), 3.22 - 3.15 (m, 2H), 2.96 (br dd, J = 12.0, 8.8 Hz, 1H), 2.22 (s, 6H).

[0296] Synthesis of compound 23-B-threo in Step 3

[0297] The intermediate 23-4-threo (337.00 mg, 890.95 μmol) was dissolved in tetrahydrofuran (12 mL), and lithium aluminum hydride (2.5 M, 1.25 mL) was slowly added dropwise to the reaction solution under the protection of N2at 0 °C. After the addition was completed, the temperature was raised to 20 °C, and stirring was performed for 40 min. After the reaction was completed by LCMS monitoring, 0.12 mL of water, 0.12 mL of 15% sodium hydroxide aqueous solution, and 0.36 mL of water were sequentially added dropwise to the reaction solution at 0 °C to quench the reaction, followed by drying with anhydrous sodium sulfate and filtering. The filter cake was washed with ethyl acetate (15 mL x 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was freeze-dried by reverse phase column chromatography (C 18 18-48% acetonitrile) to obtain compound 23-B-threo (100 mg, off-white gum, yield 30.81%). LCMS: 308.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 0.9H), 7.90 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 7.42 - 7.32 (m, 3H), 7.10 (dd, J = 8.4, 1.6 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 5.16 (d, J = 6.8 Hz, 1H), 3.36 - 3.29 (m, 2H), 2.94 (br dd, J = 12.4, 6.8 Hz, 1H), 2.79 (dd, J = 12.4, 7.6 Hz, 1H), 2.18 (s, 6H).

[0298] Example 13

[0299] Synthesis of compound 24-2 in Step 1

[0300] Compound 24-1 (8.486 g, 58.06 mmol) was dissolved in chloroform (130 mL). Then liquid bromine (14.09 g, 88.15 mmol) dissolved in chloroform (60 mL) was added slowly dropwise to the mixture under nitrogen atmosphere at -10 °C. The reaction solution was stirred at 20 °C for 1 hour. After the reaction was completed by LCMS detection, the reaction solution 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 ~ 3 / 1) to obtain compound 24-2 (16.18 g, yellow oil, yield 91.08%).

[0301] Synthesis of compound 24-3 in step 2

[0302] Compound 24-2 (16.18 g, 52.88 mmol) was dissolved in toluene (170 mL) and acetonitrile (17 mL). Then silver fluoride (53.40 g, 420.87 mmol) and benzyl bromide (2.01 g, 11.75 mmol) were added to the mixture under nitrogen atmosphere at 0 °C in the dark. The reaction solution was stirred at 20 °C in the dark under nitrogen atmosphere for 12 hours. After the reaction was completed by LCMS detection, the reaction solution was diluted with water (200 mL) at 0 °C, filtered, and the filtrate was extracted with ethyl acetate (200 mL x 3), 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 = 10 / 1 ~ 3 / 1) to obtain compound 24-3 (3.162 g, yellow oil, yield 32.47%).

[0303] Synthesis of compound 24-4 in step 3

[0304] Compound 24-3 (3.162 g, 17.17 mmol) was dissolved in dimethyl sulfoxide (80 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (12.84 g, 84.34 mmol) was added to the mixture. The reaction solution was stirred at 100 °C for 48 hours. After the reaction was completed by TLC detection, the reaction solution was diluted with water (80 mL) and then extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with brine (50 mL x 3), 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 = 10 / 1 ~ 3 / 1) to obtain compound 24-4 (1.355 g, yellow solid, yield 48.11%).

[0305] Synthesis of compound 24-5 in step 4

[0306] Potassium tert-butoxide (2.98 g, 26.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and p-toluenesulfonylmethyl isocyanide (2.57 g, 13.19 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the mixture under nitrogen protection at -70 °C, and the reaction solution was stirred at -70 °C for 15 min. Then compound 24-4 (1.355 g, 8.26 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the mixture under nitrogen protection at -70 °C, and the reaction solution was stirred at -70 °C for 1.5 h. Then anhydrous methanol (40 mL) was added to the reaction solution, and the reaction solution was stirred at 60 °C for 0.5 h. After the reaction was completed by TLC detection, the reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with water (40 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was 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 = 10 / 1 to 3 / 1) to obtain compound 24-5 (1.34 g, yellow solid, yield 92.67%).

[0307] Step 5 Synthesis of compound 24-6

[0308] Compound 24-5 (1.226 g, 7.00 mmol) was dissolved in ethanol (31 mL), and aqueous potassium hydroxide solution (5 M, 30.81 mL) was added to the mixture, and the reaction solution was stirred at 90 °C for 12 h. After the reaction was completed by TLC detection, the reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with water (30 mL) and then washed with ethyl acetate (40 mL x 3). The aqueous phase was adjusted to pH 3 with 6 M aqueous hydrochloric acid solution at 0 °C, and then extracted with ethyl acetate (50 mL x 3). The second extraction organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-6 (1.32 g, yellow solid, yield 97.13%).

[0309] Step 6 Synthesis of compound 24-7

[0310] Compound 24-6 (1.313 g, 6.76 mmol, 1 eq) was dissolved in N,N- dimethylformamide (20 mL). Then diisopropylethylamine (4.38 g, 33.86 mmol) and HATU (3.11 g, 8.17 mmol) were added to the mixture slowly under nitrogen atmosphere at 0 °C. The reaction solution was stirred at 0 °C for 5 min. Then dimethylamine hydrochloride (832 mg, 10.20 mmol) was added to the reaction solution at 0 °C. The reaction solution was stirred at 20 °C for 1 h. After the reaction was completed by LCMS detection, the reaction solution was diluted with water (30 mL) at 0 °C, then extracted with ethyl acetate (40 mL x 6), the combined organic phase was washed with saturated brine (30 mL x 3), then 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 / 1 ~ 0 / 1) to obtain compound 24-7 (1.322 g, yellow oil, yield 88.37%).

[0311] Step 7 Synthesis of compound 24-8

[0312] Compound 24-7 (651 mg, 2.94 mmol) was dissolved in anhydrous tetrahydrofuran (21 mL). Under nitrogen protection, lithium bis(trimethylsilyl)amide (1 M, 3.53 mL) was added to the mixture slowly dropwise at -70 °C. The reaction solution was stirred at -70 °C for 0.5 h. Then cyclohexanone (405 mg, 4.13 mmol) was added to the reaction solution slowly dropwise at -70 °C. After the addition was completed, the reaction solution was stirred at -70 °C for 0.5 h. After the reaction was completed by LCMS detection, 1 M aqueous hydrochloric acid (4.8 mL) was added to the reaction solution dropwise at 0 °C, then diluted with water (20 mL), extracted with ethyl acetate (40 mL x 3), the combined organic phase was washed with brine (40 mL), then 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 = 5 / 1 ~ 3 / 1) to obtain compound 24-8 (530 mg, white solid, yield 56.39%).

[0313] Step 9 Synthesis of compound 24

[0314] Compound 24-8 (484 mg, 1.52 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and a solution of borane tetrahydrofuran (1 M, 7.58 mL) was slowly added dropwise to the mixture at 0 °C under nitrogen protection. The reaction solution was stirred at 60 °C for 2 h. After the reaction was detected by LCMS, 2 M hydrochloric acid methanol solution (20 mL) was added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 20 °C for 12 h. Then the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reversed-phase chromatography column (C18 column, 0.1% trifluoroacetic acid system and 8-38% acetonitrile), and freeze-dried to obtain compound 24 (170 mg, yellow solid, yield 36.73%). Compound 24A (retention time: 1.224 min) was purified by SFC chiral separation (column type: DAICEL CHIRALPAK IC (250 mm x 50 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode). LCMS: 306.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.20 (d, J = 4.4 Hz, 1H), 8.16 (s, 0.84H), 7.52 (s, 1H), 7.48 (dd, J = 2.0, 8.4 Hz, 1H), 7.31 (dd, J = 1.6, 8.8 Hz, 1H), 3.03-2.97 (m, 2H), 2.82-2.73 (m, 1H), 2.20 (s, 6H), 1.67-0.93 (m, 11H). Compound 24B (retention time: 1.347 min). LCMS: 306.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.20 (d, J = 4.4 Hz, 1H), 8.16 (s, 0.84H), 7.52 (s, 1H), 7.48 (dd, J = 2.0, 8.4 Hz, 1H), 7.31 (dd, J = 1.6, 8.8 Hz, 1H), 3.03-2.97 (m, 2H), 2.82-2.73 (m, 1H), 2.20 (s, 6H), 1.67-0.93 (m, 11H). Compound 24B (retention time: 1.347 min). LCMS: 306.2 [M+H]

[0315] Example 14

[0316] Step 1 Synthesis of compound 25-2

[0317] Compound 25-1 (5.0 g, 35.69 mmol) was added into sulfuric acid (50 mL) at 0 °C, then N-iodosuccinimide (8.83 g, 39.25 mmol, 1.1 eq) was added in batches, after the addition was completed, the reaction liquid was stirred at 40 °C for 12 hours. After the reaction was completed by LCMS monitoring, the reaction liquid was poured into ice water (300 mL), the aqueous phase was extracted with ethyl acetate (200 mL x 3) for three times, the combined organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain a crude product, which was further washed with petroleum ether / ethyl acetate = 5 / 1 (10V) by filtration, and the filtrate was collected and concentrated to obtain compound 25-2 (3.0 g, yield 31.60%, brown solid).

[0318] Synthesis of compound 25-3

[0319] Compound 25-2 (3.0 g, 11.28 mmol), triethylamine (4.71 mL, 33.83 mmol, 3 eq), cuprous iodide (42.96 mg, 222.56 μmol, 0.02 eq) and dichlorobis(triphenylphosphine)palladium (237.48 mg, 338.34 μmol, 0.03 eq) were dissolved in tetrahydrofuran (30 mL) and replaced with nitrogen, then trimethylsilacetylene (2.22 g, 22.56 mmol, 2 eq) was added at 20 °C, and the reaction liquid was reacted at 70 °C for 12 hours. After the reaction was completed by LCMS detection, the solvent was removed under reduced pressure to obtain a crude product. The crude product was added with methanol (75 mL), diisopropylethylamine (5.90 mL, 33.85 mmol, 3 eq.) and cuprous iodide (3.22 g, 16.93 mmol, 1.5 eq.) at room temperature. The reaction liquid was reacted at 75 °C for 2 hours. After the reaction was completed by LCMS monitoring, the reaction liquid was cooled to room temperature, the mixture was poured into water (100 mL), then PE:EA = 2:1 (60 mL) was added, the mixture was filtered, then separated, the aqueous phase was continuously extracted with PE:EA = 2:1 (60 mL x 2), then the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was added with tetrahydrofuran (25 ml) and then tetrabutylammonium fluoride trihydrate (1.34 g, 4.23 mmol, 0.5 eq.), and reacted at 70 °C for 1 hour. After the reaction was completed by TLC detection, saturated aqueous ammonium chloride solution (200 mL) was added, the aqueous phase was extracted with ethyl acetate (60 mL x 3), then the combined organic phase was washed with saturated brine (200 mL) 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 / 0-10 / 1) to obtain compound 25-3 (340 mg, yield 25.4%, yellow solid).

[0320] Synthesis of compound 25-4 in step 3

[0321] Potassium tert-butoxide (743.83 mg, 6.63 mmol, 3.2 eq) was dissolved in tetrahydrofuran (8 mL), then nitrogen was replaced and cooled to -70 °C, then p-methylbenzenesulfonylmethyl isocyanide (647.09 mg, 3.31 mmol, 1.6 eq) in tetrahydrofuran (4 mL) was added, first stirred at -70 °C for 15 min, then compound 25-3 (340 mg, 2.07 mmol, 1 eq.) in tetrahydrofuran (2 mL) was added to the above solution, and the mixture was stirred at -70 °C for 1.5 h, then methanol (2 mL) was added, then slowly warmed to room temperature and stirred at 60 °C for half an hour. After TLC monitoring the reaction was completed, the reaction solution was added to water (60 mL), the aqueous phase was extracted with ethyl acetate (30 mL) three times, the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-8 / 1) to give compound 25-4 (270 mg, yield 73.16%, yellow oil).

[0322] Synthesis of compound 25-5 in step 4

[0323] Compound 25-4 (200 mg, 1.14 mmol, 1 eq) was dissolved in ethanol (5 mL), then potassium hydroxide (5 M, 5.02 mL, 22 eq) aqueous solution was added, and the reaction was reacted at 90 °C for 12 h. After TLC detection of the complete reaction of the raw material, the reaction solution was added to 1 N aqueous hydrochloric acid solution (50 mL), the aqueous phase was extracted with ethyl acetate (20 mL) three times, the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 25-5 (220 mg, yield 99.24%, yellow solid).

[0324] Synthesis of compound 25-6 in step 5

[0325] Compound 25-5 (220 mg, 1.13 mmol, 1 eq) was dissolved in DMF (3 mL) and DIEA (986.82 μL, 5.67 mmol, 5 eq) was added, then nitrogen was replaced and cooled to 0 °C, then HATU (473.92 mg, 1.25 mmol, 1.1 eq) was added, after addition, 0 °C was stirred for 5 min, then dimethylamine hydrochloride (138.60 mg, 1.70 mmol, 1.5 eq) was added to the reaction solution, and the reaction solution was slowly warmed to 20 °C for 1 h. After the reaction was completed by LCMS detection, the reaction solution was directly passed through the reverse phase (formic acid) to obtain compound 25-6 (210 mg, yield 83.31%, white solid).

[0326] Step 6 synthesis of compound 25-7

[0327] Compound 25-6 (210 mg, 949.25 μmol, 1 eq.) was dissolved in anhydrous tetrahydrofuran (4 mL) and nitrogen was replaced, cooled to -70 °C, then lithium bis(trimethylsilyl)amide (1 M, 1.14 mL, 1.2 eq) was added dropwise, after dropwise addition, -70 °C was stirred for 30 min. Cyclohexanone (139.74 mg, 1.42 mmol, 1.5 eq) was dissolved in anhydrous tetrahydrofuran (4 mL) and added dropwise to the reaction solution under nitrogen protection at -70 °C, after dropwise addition, it was stirred at -70 °C for 30 min. After the reaction was completed by LCMS monitoring, the reaction solution was added to saturated aqueous ammonium chloride solution (80 mL) to quench the reaction, and the reaction solution was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain compound 25-7 (160 mg, yield 52.78%, white solid).

[0328] Step 7 synthesis of compound 25

[0329] Compound 25-7 (160 mg, 500.99 μmol) was dissolved in tetrahydrofuran (4 mL), lithium aluminum hydride (2.5 M, 701.38 μL) was added slowly dropwise under nitrogen protection at 0 °C, and the mixture was stirred at 20 °C for half an hour. After monitoring the end of the reaction by LCMS, the reaction solution was first diluted with 4 mL of tetrahydrofuran, and then 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 under ice bath conditions. Filtration, collection of the filtrate, and concentration of the filtrate under reduced pressure gave a crude product, which was purified by reverse phase separation (0.1% ammonia water system) to give compound 25, which was then separated by SFC (column type: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to give compound 25A (retention time: 0.871 min, 11.44 mg, yield 7.62%, white solid). LCMS: 306.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.95 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 10.4 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 4.81 (br. s, 1H), 3.27 - 3.22 (m, 1H), 2.87 - 2.82 (m, 1H), 2.63 - 2.57 (m, 1H), 2.08 (s, 6H), 1.71 - 1.68 (m, 1H), 1.58 - 1.43 (m, 3H), 1.38 - 1.23 (m, 3H), 1.21 - 1.12 (m, 2H), 1.05 - 0.95 (m, 1H). Compound 25B (retention time: 1.204 min, 11.24 mg, yield 7.34%, white solid). LCMS: 306.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.95 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 10.4 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 4.81 (br. s, 1H), 3.27 - 3.22 (m, 1H), 2.87 - 2.82 (m, 1H), 2.63 - 2.57 (m, 1H), 2.08 (s, 6H), 1.71 - 1.68 (m, 1H), 1.58 - 1.43 (m, 3H), 1.38 - 1.23 (m, 3H), 1.21 - 1.12 (m, 2H), 1.05 - 0.95 (m, 1H). Compound 25B (retention time: 1.204 min, 11.24 mg, yield 7.34%, white solid). LCMS: 306.2 [M+H]

[0330] Example 15

[0331] Synthesis of compound 26-2

[0332] The starting material 26-1 (5 g, 25.38 mmol) was dissolved in tetrahydrofuran (50 mL), and LDA (15.23 mL, 2 M) was added under nitrogen protection at -70 °C. The reaction solution was reacted for half an hour under nitrogen protection at -70 °C, and then methyl iodide (5.4 g, 38.07 mmol) was added to the above reaction solution and reacted for 1 hour under nitrogen protection at -70 °C. The temperature was naturally increased to 25 °C and stirred for 1 hour at 25 °C. The reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then 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 / 0-10 / 1) to obtain intermediate 26-2 (2.9 g, light yellow oil, yield 54.15%). 1 H NMR (400 MHz, CHLOROFORM-d) d = 7.59 (d, J = 1.6 Hz, 1H), 7.28-7.27 (m, 1H), 7.27-7.26 (m, 1H), 6.32 (s, 1H), 2.45 (s, 3H).

[0333] Synthesis of compound 26-4

[0334] Intermediate 26-2 (2 g, 9.48 mmol) was dissolved in DMF (30 mL), and 26-3 (5.35 g, 28.43 mmol), anhydrous zinc fluoride (2.94 g, 28.43 mmol), bis(triphenylphosphine)palladium(0) (484 mg, 0.947 mmol) were slowly added, and stirred at 120 °C for 12 hours after nitrogen replacement. After the reaction was completed by TLC monitoring, the reaction solution was poured into 100 mL of an aqueous solution, and then extracted with 100 mL of ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was collected, 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 / 0-5 / 1) to obtain intermediate 26-4 (1.2 g, light yellow oil, yield 62.01%).

[0335] Synthesis of compound 26-5

[0336] Intermediate 26-4 (1.1 g, 5.38 mmol) was dissolved in methanol (1 mL), and dimethylamine methanol solution (21.55 mL, 2M, 43.12 mmol) was added slowly. After nitrogen protection for 4 hours at 70°C, the reaction was monitored by LCMS. After the reaction was completed, the reaction solution was concentrated, and then purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 26-5 (800 mg, white solid, yield 67.68%).

[0337] Step 4 synthesis of compound 26-6

[0338] Intermediate 26-5 (800 mg, 3.68 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (8 mL) under nitrogen protection, and LiHMDS (1M, 3.68 mL, 1.0 eq) was added dropwise at -78°C. After the addition was completed, the mixture was stirred at -78°C for 30 minutes. Cyclohexanone (433 mg, 4.42 mmol, 1.2 eq) was dissolved in anhydrous tetrahydrofuran (4 mL), and the solution was added dropwise to the reaction solution under nitrogen protection at -78°C. After the addition was completed, the mixture was stirred at -78°C for 30 minutes. After the reaction was completed, the mixture was quenched by slowly adding hydrochloric acid (4.6 mL, 1N) at -78°C, and the reaction solution was slowly warmed to 20°C and stirred for 1 hour. Water (20 mL) was added, and the reaction solution was extracted with ethyl acetate (90 mL, 30 mL x 3). The combined organic phase was washed with saturated brine (45 mL, 15 mL x 3), 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 = 20 / 1-2 / 1) to obtain intermediate 26-6 (900 mg, yield 77.49%, white solid).

[0339] Step 5 synthesis of compound 26

[0340] Intermediate 26-6 (500 mg, 1.59 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (2.5M, 1.9 mL) was added dropwise slowly at 0°C under nitrogen protection. The mixture was stirred at 20°C for half an hour. After the reaction was completed, the reaction solution was diluted with 5 mL of tetrahydrofuran, and then 0.2 mL of water, 0.2 mL of 15% sodium hydroxide aqueous solution, 0.4 mL of water, and anhydrous sodium sulfate were added slowly and successively to the reaction solution under ice bath conditions. The mixture was filtered, and the filtrate 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 15-45% acetonitrile), and then freeze-dried to obtain 26 (180 mg, white viscous material, yield 30.07%). LCMS: 302.1 [M+H] + . 1 ​​​​H NMR (400 MHz, DMSO-d6) d = 8.20 (s, 1H), 7.38 - 7.30 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 3.10 (dd, J = 7.2, 12.4 Hz, 1H), 2.92 (t, J = 7.6 Hz, 1H), 2.65 (dd, J = 7.4, 12.4 Hz, 1H), 2.41 (s, 3H), 2.21 (s, 6H), 1.63 - 1.27 (m, 7H), 1.20 - 1.01 (m, 2H), 0.96 - 0.86 (m, 1H).

[0341] Synthesis of compound 26-A and 26-B

[0342] Compound 26 (160 mg, 530 pmol) was separated by SFC (column type: DAICEL CHIRALPAK IK (250 mm x 50 mm, 10 pm) E; mobile phase: [C02-i-PrOH (0.1% NH3H20]; B%: 18%, isocratic elution mode) to give a crude product, which was then purified by reverse phase separation method (0.1% formic acid system and 15-45% acetonitrile) to give compound 26-A (retention time: 1.241 min, 40 mg, white sticky material, yield 21.69%). LCMS: 302.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d = 7.37 - 7.29 (m, 2H), 7.07 (dd, J = 1.6, 8.4 Hz, 1H), 6.50 (s, 1H), 3.08 (dd, J = 7.3, 12.4 Hz, 1H), 2.91 (t, J = 7.3 Hz, 1H), 2.62 (dd, J = 7.3, 12.3 Hz, 1H), 2.41 (d, J = 0.8 Hz, 3H), 2.20 (s, 6H), 1.62 - 1.27 (m, 7H), 1.20 - 1.00 (m, 2H), 0.97 - 0.84 (m, 1H). Compound 26-B (retention time: 0.853 min, 41 mg, white sticky material, yield 22.03%). 1H NMR (400 MHz, DMSO-d6) d = 7.34 (s, 2H), 7.07 (dd, J = 1.4, 8.4 Hz, 1H), 6.50 (s, 1H), 3.08 (d, J = 5.0 Hz, 1H), 2.91 (t, J = 7.3 Hz, 1H), 2.61 (dd, J = 7.4, 12.5 Hz, 1H), 2.42 (s, 3H), 2.19 (s, 6H), 1.61 - 1.26 (m, 7H), 1.20 - 1.01 (m, 2H), 0.96 - 0.84 (m, 1H).

[0343] Example 16

[0344] Synthesis of compound 28-2

[0345] Compound 28-1 (460 mg, 2.13 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), under nitrogen protection, lithium bis (trimethylsilyl) amide (1 M, 3.19 mL) was slowly added dropwise into the mixture at -70 °C, the reaction solution was stirred at -70 °C for 0.5 h, then cyclohexanone (334 mg, 3.40 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), slowly added dropwise into the reaction solution at -70 °C, after the addition was completed, it was stirred at -70 °C for 0.5 h. After the reaction was completed by LCMS detection, 1 M aqueous hydrochloric acid (5 mL) was added dropwise into the reaction solution below -30 °C, diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 3), the organic phase was washed with brine (20 mL), then 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 = 5 / 1 ~ 3 / 1) to obtain intermediate 28-2 (610 mg, white solid, yield 91.22%). LCMS: 337.0 [M+Na] + .

[0346] Synthesis of compound 28

[0347] Aluminum trichloride (248 mg, 1.86 mmol) was suspended in tetrahydrofuran (15 mL), under the protection of nitrogen, lithium aluminum hydride (2.5 M, 2.19 mL) was slowly added to the reaction solution at 0 °C, after the addition was completed, it was stirred at 0 °C for 15 min. Then intermediate 28-2 (573 mg, 1.82 mmol) was dissolved in tetrahydrofuran (5 mL), slowly added to the reaction solution at 0 °C under the protection of nitrogen, after the addition was completed, it was warmed to 10 °C and stirred for 30 min. After monitoring the reaction completion by LCMS, 0.21 mL of water, 0.21 mL of 15% sodium hydroxide aqueous solution and 0.63 mL of water were added to the reaction solution at 0 °C to quench the reaction, then anhydrous sodium sulfate was added to dryness, filtered, the filter cake was washed with ethyl acetate (20 mL x 3), the filtrate was collected and concentrated under reduced pressure to obtain a crude product. The crude product was freeze-dried by reversed-phase chromatography column (0.1% formic acid system and 20-33% acetonitrile) to obtain compound 28 (461.01 mg, white gum, yield 84.20%). LCMS: 301.2 [M+H] 18 . + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.38 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.04 (dd, J = 1.2, 8.4 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 3.76 (s, 4H), 3.27 (dd, J = 7.6, 12.4 Hz, 1H), 2.95 (t, J = 7.2 Hz, 1H), 2.73 (dd, J = 7.2, 12.4 Hz, 1H), 2.29 (s, 6H), 1.62-1.14 (m, 9H), 1.10-0.99 (m, 1H), 0.93-0.79 (m, 1H).

[0348] Synthesis of compound 28-A and 28-B

[0349] Compound 28 (461 mg, 1.53 mmol) was subjected to chiral resolution (column type: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) to obtain compound 28-A (retention time: 1.599 min, 135.67 mg, yield 29.43%, white gum). LCMS: 301.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.36 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.07-6.98 (m, 1H), 6.34 (d, J = 3.2 Hz, 1H), 3.75 (s, 3H), 3.22 (br dd, J = 8.0, 12.4 Hz, 1H), 2.93 (br t, J = 7.4 Hz, 1H), 2.66-2.61 (m, 1H), 2.25 (s, 6H), 1.60-1.14 (m, 8H), 1.09-0.95 (m, 1H), 0.92-0.77 (m, 1H).

[0350] Compound 28-B (Retention time: 1.836 min, 150.04 mg, 32.62% yield, white gum) 1 H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.36 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 7.03 (dd, J = 1.4, 8.4 Hz, 1H), 6.35 (dd, J = 0.8, 2.8 Hz, 1H), 3.76 (s, 3H), 3.22 (br dd, J = 8.0, 12.4 Hz, 1H), 2.93 (t, J = 7.4 Hz, 1H), 2.62 (br dd, J = 7.0, 12.6 Hz, 1H), 2.25 (s, 6H), 1.60-1.16 (m, 8H), 1.09-0.97 (m, 1H), 0.95-0.76 (m, 1H).

[0351] Example 17

[0352] Synthesis of compound 29-2

[0353] Compound 29-1 (10 g, 57.08 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL), then pyridine (50 mL) and Selectfluor reagent (30.33 g, 85.62 mmol, 1.5 eq) were added in batches at 0 °C, and the reaction solution was stirred at 20 °C for 1 h. After TLC detection showed that the reaction was complete, the reaction solution was added to water (200 mL), and the aqueous phase was extracted with ethyl acetate (200 mL x 3), then the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-3 / 1) to give intermediate 29-2 (4.6 g, yield 32.80%, white solid).

[0354] Synthesis of compound 29-3 in step 2

[0355] The intermediate 29-2 (3.2 g, 16.57 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL) and then replaced with nitrogen. Sodium hydride (795.14 mg, 19.88 mmol, 60% purity, 1.2 eq) was added at 0°C, and then the reaction was carried out at 0°C for 0.5 hours. Then iodomethane (2.82 g, 19.88 mmol, 1.2 eq) was added at 0°C, and the reaction was carried out at 20°C for 1 hour. After TLC detection showed that the reaction was complete, saturated aqueous ammonium chloride solution (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 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 a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain the intermediate 29-3 (3.0 g, yield 87.40%, yellow solid).

[0356] Synthesis of compound 29-4 in step 3

[0357] Morphine (2.55 mL, 28.96 mmol, 2.0 eq) was dissolved in tetrahydrofuran (20 mL), and then DIBAL-H (28.96 mL, 1M, 28.96 mmol, 2.0 eq) was added at 0°C under nitrogen protection. The reaction was stirred at 0°C under nitrogen protection for 1 hour, and then the 29-3 (3.0 g, 14.48 mmol, 1.0 eq) tetrahydrofuran (20 mL) solution was added to the above reaction. After stirring for 20 minutes, diisobutylaluminum hydride (14.48 mL, 1M, 14.48 mmol, 1.0 eq) was added, and the reaction was continued to stir for 20 minutes. After LCMS monitoring showed that the reaction was complete, the reaction was added to hydrochloric acid aqueous solution (300 mL, 1N), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (300 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 the intermediate 29-4 (1.6 g, yield 48.84%, yellow solid).

[0358] Synthesis of compound 29-5 in step 4

[0359] Potassium tert-butoxide (3.24 g, 10.78 mmol, 3.2 eq) was dissolved in tetrahydrofuran (30 mL), then nitrogen was replaced and cooled to -70 °C, then a solution of p-toluenesulfonylmethyl isocyanide (2.82 g, 14.45 mmol, 1.6 eq) in tetrahydrofuran (15 mL) was added, first stirred at -70 °C for 15 min, then a solution of 29-4 (1.6 g, 9.03 mmol, 1 eq) in tetrahydrofuran (15 mL) was added to the above solution at -70 °C, and the mixture was stirred at -70 °C for 1.5 h, then methanol (10 ml) was added, then slowly warmed to room temperature and stirred at 60 °C for half an hour. After TLC monitoring, the reaction was completed, the reaction solution was added to water (200 mL), the aqueous phase was extracted with ethyl acetate (60 mL) three times, the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-4 / 1) to obtain intermediate 29-5 (1.1 g, yield 67.42%, yellow oil).

[0360] Step 5 Synthesis of compound 29-6

[0361] Intermediate 29-5 (200 mg, 1.01 mmol, 1 eq) was dissolved in ethanol (4 mL), then a solution of potassium hydroxide (5 M, 4 mL, 20 eq) was added, and the reaction was reacted at 90 °C for 12 h. After TLC detection, the raw material was completely reacted, the reaction solution was added to 1 N aqueous hydrochloric acid (50 mL), the aqueous phase was extracted with ethyl acetate (20 mL) three times, the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate 29-6 (140 mg, yield 66.93%, yellow solid).

[0362] Step 6 Synthesis of compound 29-7

[0363] Intermediate 29-6 (140 mg, 0.675 mmol, 1 eq) and dimethylamine (2 M, 0.405 mL, 1.2 eq) were dissolved in tetrahydrofuran (2 mL), then diisopropylethylamine (470 μL, 2.70 mmol, 4 eq) and 1-butylphosphonic anhydride (0.584 mg, 0.810 mmol, 1.2 eq) were added at 0 °C, and the reaction was slowly warmed to 20 °C for 1 h. After LCMS detection, the reaction was completely reacted, the reaction solution was rotary evaporated, and then purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 29-7 (140 mg, yield 87.27%, yellow oil).

[0364] Step 7 Synthesis of compound 29-8

[0365] Intermediate 29-7 (140 mg, 0.598 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (2 mL) and replaced with nitrogen, and LiHMDS (1 M, 0.896 mL, 1.5 eq) was added dropwise while cooling to -70 °C. After the dropwise addition was completed, the mixture was stirred at -70 °C for 30 min. Cyclohexanone (87.98 mg, 0.896 mmol, 1.5 eq) was dissolved in anhydrous tetrahydrofuran (2 mL) and added dropwise to the reaction mixture under nitrogen protection at -70 °C. After the dropwise addition was completed, the mixture was stirred at -70 °C for 30 min. After the reaction was completed by TLC monitoring, the reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (40 mL) below -30 °C, and the reaction was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 - 4 / 1) to obtain intermediate 29-8 (150 mg, yield 75.51%, white solid).

[0366] Step 8 Synthesis of compounds 29-A / 29-B

[0367] Aluminum trichloride (60.17 mg, 0.451 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (2.5 M, 0.451 mL, 2.5 eq) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 0 °C for 15 min, and then a tetrahydrofuran (2 mL) solution of intermediate 29-8 (150 mg, 0.451 mmol, 1.0 eq.) was added. After the addition was completed, the reaction was continued at 0 °C for half an hour. After the reaction was completed by LCMS monitoring, the reaction was diluted with 4 mL of tetrahydrofuran, and then 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 mixture under ice bath conditions. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by SFC separation method (column type: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to obtain compound 29A (retention time: 1.144 min, 13.53 mg, yield 10.41%, white solid) and compound 29B (retention time: 1.366 min, 15.40 mg, yield 11.85%, white solid).

[0368] Compound 29A: 1H NMR (400 MHz, CDC13) δ 8.47 (br. s, 1H), 7.42 (s, 1H), 7.22 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 3.95 - 3.92 (m, 1H), 3.72 (s, 3H), 3.31 (t, J = 2.0 Hz, 1H), 2.99 - 2.96 (m, 1H), 2.54 (s, 6H), 1.76 - 1.64 (m, 3H), 1.58 - 1.41 (m, 4H), 1.35 - 1.28 (m, 1H), 1.19 - 1.12 (m, 1H), 0.95 - 0.83 (m, 1H). LCMS: 319.3 [M+H] + .

[0369] Compound 29B: 1 H NMR (400 MHz, CDC13) δ 8.47 (br. s, 1H), 7.42 (s, 1H), 7.22 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 3.95 - 3.92 (m, 1H), 3.72 (s, 3H), 3.31 (t, J = 2.0 Hz, 1H), 2.99 - 2.96 (m, 1H), 2.54 (s, 6H), 1.76 - 1.64 (m, 3H), 1.58 - 1.41 (m, 4H), 1.35 - 1.28 (m, 1H), 1.19 - 1.12 (m, 1H), 0.95 - 0.83 (m, 1H). LCMS: 319.3 [M+H] + .

[0370] Example 18

[0371] Synthesis of compound 30-2

[0372] The starting material 30-1 (45 g, 291.95 mmol, 1.0 eq) was added to sulfuric acid (450 mL) at 0 °C, then NIS (72.25 g, 321.14 mmol, 1.1 eq) was added in batches, and after the addition was completed, the reaction liquid was stirred at 20 °C for 1 hour. After the reaction was completed by HPLC monitoring, the reaction liquid was added to ice water (2000 mL), and the aqueous phase was extracted with ethyl acetate (800 mL x 3) three times, and the combined organic phase was washed with saturated brine (2000 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the intermediate 30-2 (85.0 g, yield 96.37%, brown solid).

[0373] Synthesis of compound 30-3

[0374] Intermediate 30-2 (85 g, 303.53 mmol, 1.0 eq) was dissolved in methanol (500 mL) and then sulfuric acid (1.49 g, 15.18 mmol, 0.05 eq) was added at 20 °C. The reaction solution was reacted at 70 °C for 48 h. After the reaction was completed by LCMS detection, the solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-50 / 1) to obtain intermediate 30-3 (81.0 g, yield 90.8%, brown solid).

[0375] Step 3 Synthesis of compound 30-4

[0376] Intermediate 30-3 (10 g, 34.01 mmol, 1.0 eq) was dissolved in DMSO (100 mL) and then ethyl difluorobromoacetate (17.26 g, 85.02 mmol, 2.5 eq) and copper powder (6.48 g, 102.02 mmol, 3.0 eq) were added portionwise under nitrogen protection. After the addition was completed, the reaction solution was stirred at 60 °C for 12 h under nitrogen protection. After the reaction was completed by HPLC detection, the reaction solution was added to water (200 mL) and ethyl acetate (200 mL), and a large amount of solid was precipitated. The mixture was filtered with diatomite, and then separated into two phases. The aqueous phase was extracted twice with ethyl acetate (200 mL x 2), and the combined organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-8 / 1) to obtain intermediate 30-4 (9.4 g, yield 95.24%, colorless oil).

[0377] Step 4 Synthesis of compound 30-5

[0378] Intermediate 30-4 (9.4 g, 32.39 mmol, 1.0 eq) was dissolved in ethanol (200 mL) and then sodium borohydride (1.23 g, 32.39 mmol, 1.0 eq) was added portionwise under nitrogen protection at 0 °C. After the addition was completed, the reaction solution was stirred at 0 °C for 1 h under nitrogen protection. After the reaction was completed by LCMS detection, saturated aqueous ammonium chloride solution (300 mL) was added dropwise to the reaction solution, and the aqueous phase was extracted three times with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-8 / 1) to obtain intermediate 30-5 (7.0 g, yield 87.08%, white solid).

[0379] Step 5 Synthesis of compound 30-6

[0380] Intermediate 30-5 (3.0 g, 12.09 mmol, 1.0 eq) and 18-crown-6 (1.60 g, 6.04 mmol, 0.5 eq.) were dissolved in tetrahydrofuran (30 mL), and then sodium tert-butoxide (1 N, 25.38 mL, 2.1 eq) was added under nitrogen protection at 20 °C. After the addition was completed, the reaction solution was stirred at 20 °C under nitrogen protection for 2 h. After the reaction was completed by LCMS monitoring, the reaction solution was added to water (310 mL), and the aqueous phase was extracted with ethyl acetate (60 mL x 3) three times. The combined organic phase was washed with saturated brine (100 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 30-6 (2.0 g, yield 79.48%, white solid).

[0381] Step 6 Synthesis of compound 30-7

[0382] Morpholine (1.52 mL, 17.29 mmol, 2.0 eq) was dissolved in tetrahydrofuran (20 mL), and then diisobutylaluminum hydride (1 M, 17.29 mmol, 2.0 eq) was added under nitrogen protection at 0 °C. The reaction solution was stirred at 0 °C under nitrogen protection for 2 h, and then a solution of intermediate 30-6 (1.8 g, 8.65 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added to the above reaction solution. After stirring for 10 min, diisobutylaluminum hydride (1 M, 8.65 mmol, 1.0 eq) was added, and the reaction solution was continuously stirred for 20 min. After the reaction was completed by LCMS monitoring, hydrochloric acid aqueous solution (100 mL, 1 N) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (80 mL x 3) three times. The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by reverse phase (0.1% FA aqueous solution-acetonitrile) to obtain intermediate 30-7 (700 mg, yield 45.44%, white solid).

[0383] Step 7 Synthesis of compound 30-8

[0384] Potassium tert-butoxide (1.21 g, 10.78 mmol, 3.2 eq) was dissolved in tetrahydrofuran (10 mL), then nitrogen was replaced and cooled to -70 °C, then p-methylbenzenesulfonylmethyl isocyanide (1.05 g, 5.39 mmol, 1.6 eq) was added in tetrahydrofuran (5 mL) solution, first stirred at -70 °C for 15 min, then the intermediate 30-7 (600 mg, 3.37 mmol, 1 eq) was added in tetrahydrofuran (5 mL) solution at -70 °C, the mixture was stirred at -70 °C for 1.5 h, then methanol (3 ml) was added, then slowly warmed to room temperature and stirred at 60 °C for half an hour. After TLC monitoring the reaction was completed, the reaction solution was added to water (60 mL), the aqueous phase was extracted with ethyl acetate (30 mL) three times, the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-8 / 1) to obtain intermediate 30-8 (600 mg, yield 94.17%, yellow oil).

[0385] Step 8 Synthesis of compound 30-9

[0386] Intermediate 30-8 (600 mg, 3.17 mmol, 1 eq) was dissolved in ethanol (10 mL), then a potassium hydroxide (5 M, 10 mL, 22 eq) aqueous solution was added, and the reaction solution was reacted at 90 °C for 12 h. After TLC detection of the complete reaction of the raw material, 1 N hydrochloric acid aqueous solution (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL) three times, the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate 30-9 (650 mg, yield 98.45%, yellow solid).

[0387] Step 9 Synthesis of compound 30-10

[0388] Intermediate 30-9 (360 mg, 1.73 mmol, 1 eq) and dimethylamine (2 N, 0.951 mL, 1.1 eq) were dissolved in tetrahydrofuran (3 mL), then DIEA (986.82 μL, 5.67 mmol, 5 eq) was added at 0 °C, then nitrogen was replaced and cooled to 0 °C, then 1-butylphosphonic anhydride (1.50 g, 2.08 mmol, 1.2 eq) was added, and after the addition was completed, the reaction solution was slowly warmed to 20 °C and reacted for 1 h. After LCMS detection of the complete reaction, the reaction solution was rotary evaporated, and then purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-2 / 1) to obtain intermediate 30-10 (330 mg, yield 79.76%, colorless oil).

[0389] Step 10 Synthesis of compound 30-11

[0390] Intermediate 30-10 (330 mg, 1.40 mol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4 mL) and replaced with nitrogen, and cooled to -70 °C. Lithium bis(trimethylsilyl)amide (1 M, 2.10 mL, 1.5 eq) was added dropwise, and after the addition was completed, it was stirred at -70 °C for 30 min. Cyclohexanone (206.50 mg, 2.10 mmol, 1.5 eq) was dissolved in anhydrous tetrahydrofuran (2 mL) and added dropwise to the reaction solution under nitrogen protection at -70 °C, and after the addition was completed, it was stirred at -70 °C for 30 min. After the reaction was completed by TLC monitoring, the reaction solution was added to saturated aqueous ammonium chloride solution (40 mL) to quench the reaction, and the reaction solution was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 - 8 / 1) to obtain intermediate 30-11 (410 mg, yield 87.11%, white solid).

[0391] Synthesis of compound 30A / 30B

[0392] Aluminum trichloride (135.98 mg, 1.02 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL), and then lithium aluminum hydride (2.5 M, 1.02 mL, 2.5 eq) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 0 °C for 15 min, and then a tetrahydrofuran (4 mL) solution of intermediate 11 (340 mg, 1.02 mmol, 1.0 eq) was added. After the addition was completed, the reaction was continued at 0 °C for half an hour. After the reaction was completed by LCMS monitoring, the reaction solution was first diluted with 4 mL of tetrahydrofuran, and then 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 under ice bath conditions. Filtration was performed, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase preparative separation (column type: Phenomenex luna C18 150 x 25 mm, 10 μm; mobile phase: [H2O (0.225% FA) - ACN]; gradient elution: 8% - 38% B over 9.0 min) to obtain compound 30 (180.23 mg, yield 48.36%, white solid). Then, SFC resolution was performed (column type: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 20%, isocratic elution mode), and then freeze-drying was performed to obtain compound 30A (retention time: 1.284 min, 54.13 mg, white solid) and compound 30B (retention time: 1.412 min, 61.10 mg, white solid).

[0393] Compound 30A:1 H NMR (400 MHz, CDC13) δ 8.39 (s, 1H), 7.62 (d, J = 4.4 Hz, 1H), 7.26-7.22 (m, 1H), 7.00 (s, 1H), 4.02 (dd, J = 4.8, 12.8 Hz, 1H), 3.34 (t, J = 5.6 Hz, 1H), 3.08 (dd, J = 6.2, 12.8 Hz, 1H), 2.62 (s, 6H), 2.50 (s, 3H), 1.77-1.43 (m, 7H), 1.28-1.16 (m, 2H), 0.90-0.87 (m, 1H). LCMS: 320.3 [M+H] + .

[0394] Compound 30B: 1 H NMR (400 MHz, CDC13) δ 8.39 (s, 1H), 7.62 (d, J = 4.4 Hz, 1H), 7.26-7.22 (m, 1H), 7.00 (s, 1H), 4.02 (dd, J = 4.8, 12.8 Hz, 1H), 3.34 (t, J = 5.6 Hz, 1H), 3.08 (dd, J = 6.2, 12.8 Hz, 1H), 2.62 (s, 6H), 2.50 (s, 3H), 1.77-1.43 (m, 7H), 1.28-1.16 (m, 2H), 0.90-0.87 (m, 1H). LCMS: 320.3 [M+H] + .

[0395] Example 19

[0396] Compound 31 was obtained using the same synthetic method as compound 28, then purified by SFC chiral separation (column type: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 30%, isocratic elution mode) to obtain compound 31A (retention time: 1.247 min), 1H NMR (400 MHz, DMSO-d6) δ 10.95 (br s, 1H), 8.21 (s, 1H), 7.35 (s, 1H), 7.30-7.23 (m, 2H), 6.95 (dd, J = 1.2, 8.4 Hz, 1H), 6.35 (s, 1H), 3.23 (dd, J = 8.4, 12.8 Hz, 1H), 2.92 (t, J = 7.2 Hz, 1H), 2.62 (dd, J = 6.8, 12.4 Hz, 1H), 2.26 (s, 6H), 1.65-1.16 (m, 9H), 1.10-0.98 (m, 1H), 0.93-0.77 (m, 1H). LCMS: 287.2 [M+H] + and compound 31B (retention time: 1.367 min). 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (br s, 1H), 8.21 (s, 1H), 7.35 (s, 1H), 7.30-7.23 (m, 2H), 6.95 (dd, J = 1.2, 8.4 Hz, 1H), 6.35 (s, 1H), 3.23 (dd, J = 8.4, 12.8 Hz, 1H), 2.92 (t, J = 7.2 Hz, 1H), 2.62 (dd, J = 6.8, 12.4 Hz, 1H), 2.26 (s, 6H), 1.65-1.16 (m, 9H), 1.10-0.98 (m, 1H), 0.93-0.77 (m, 1H). LCMS: 287.2 [M+H] + .

[0397] Example 20

[0398] Synthesis of compound 39-2

[0399] Intermediate 39-1 (170 mg, 768.44 pmol) was dissolved in anhydrous tetrahydrofuran (6 mL), under the protection of nitrogen, lithium bis(trimethylsilyl)amide (1 M, 1.15 mL) was slowly added dropwise to the mixture at -70 °C, the reaction solution was stirred at -70 °C for 0.5 h, then cyclohexylcarbinol (138 mg, 1.23 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), slowly added dropwise to the reaction solution at -70 °C, after the addition was completed, it was stirred at -70 °C for 0.5 h. After the reaction was completed by LCMS detection, 1 M aqueous hydrochloric acid (2 mL) was added dropwise to the reaction solution at 0 °C, diluted with water (10 mL), then extracted with ethyl acetate (20 mL x 3), the organic phase was washed with brine (10 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was freeze-dried by reversed-phase chromatography column (C18 column, 0.1% formic acid system and 70-90% acetonitrile) to obtain intermediate 39-2 (162 mg, yellow oil, yield 63.23%).

[0400] Synthesis of compounds 39A (erythro) and 39B (threo)

[0401] Intermediate 39-2 (142 mg, 425.92 pmol) was dissolved in anhydrous tetrahydrofuran (5 mL), under the protection of nitrogen, borane tetrahydrofuran solution (1 M, 2.13 mL) was slowly added dropwise to the mixture at 0 °C, the reaction solution was stirred at 60 °C for 2 h. After the reaction was completed by LCMS detection, 2 M hydrochloric acid in methanol (15 mL) was added dropwise to the reaction solution at 0 °C, the reaction solution was stirred at 25 °C for 12 h. Then the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was freeze-dried by reversed-phase chromatography column (C18 column, 0.05% ammonia system and 55-85% acetonitrile) to obtain compound 39A (erythro) (40 mg, yellow gum, yield 23.52%), 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.61-7.55 (m, 2H), 7.36 (s, 2H), 3.68 (td, J = 4.0, 8.0 Hz, 1H), 3.19-3.12 (m, 1H), 2.85 (dd, J = 8.4, 12.0 Hz, 1H), 2.75 (br d, J = 4.8 Hz, 1H), 2.56 (dd, J = 6.8, 12.4 Hz, 1H), 2.24 (s, 6H), 1.97 (br d, J = 11.6 Hz, 1H), 1.70-1.63 (m, 3H), 1.39-1.33 (m, 2H), 1.28-1.22 (m, 1H), 1.15-1.07 (m, 4H), LCMS: 320.3 [M+H] +and compound 39B (threo) (20 mg, yellow solid, yield 13.23%), 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.60 (d, J = 4.8 Hz, 1H), 7.49 (s, 1H), 7.40-7.33 (m, 2H), 7.12 (d, J = 9.6 Hz, 1H), 3.94 (br d, J = 8.4 Hz, 1H), 3.13-2.98 (m, 2H), 2.40 (br d, J = 10.4 Hz, 1H), 2.35 (s, 6H), 1.70-1.63 (m, 3H), 1.47-1.42 (m, 1H), 1.38-1.27 (m, 3H), 1.14-0.97 (m, 4H). LCMS: 320.3 [M+H] + .

[0402] Example 21

[0403] Step 1 synthesis of compound 64-2

[0404] The starting material 64-1 (10 g, 61.67 mmol, 1 eq) and N,N-dimethylformamide (450.80 mg, 6.17 mmol, 474.53 μL, 0.1 eq) were dissolved in dichloromethane (100 mL), and oxalyl chloride (9.39 g, 74.01 mmol, 6.48 mL, 1.2 eq) was slowly added dropwise under nitrogen protection at 0 °C, and then the reaction solution was reacted at 20 °C for 1 hour. Then it was cooled to 0 °C, and pyridine (14.59 g, 184.40 mmol, 14.88 mL, 3 eq) and methoxymethylamine hydrochloride (7.19 g, 73.76 mmol, 1.2 eq) were sequentially added to the reaction solution, and then the reaction solution was reacted at 20 °C for 1 hour. The reaction solution was directly spin-dried to obtain the crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to obtain the intermediate 64-2 (12.1 g, yield 95.93%, yellow oil).

[0405] Step 2 synthesis of compound 64-5

[0406] Intermediate 64-2 (11.5 g, 56.04 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL), and vinylmagnesium bromide (1 M, 112.08 mL, 2 eq) was added dropwise slowly under nitrogen protection at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS monitoring showed that the raw material was consumed completely to give a tetrahydrofuran solution of compound 64-3. Then the reaction solution was cooled to 0 °C, and aqueous methylamine (43.29 g, 557.56 mmol, 10 eq) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS monitoring showed that the raw material was consumed completely to give a tetrahydrofuran solution of compound 64-4. Then the reaction solution was cooled to 0 °C, and di-tert-butyl dicarbonate (36.40 g, 166.80 mmol, 38.32 mL, 3 eq) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS detection showed that the reaction was completed, and the reaction solution was rotary dried. Then the crude product was diluted with 500 mL of ethyl acetate and 1 L of 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (500 mL x 3), and the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and rotary dried to give a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to give intermediate 64-5 (8 g, 47.06% yield of three steps, yellow solid).

[0407] Step 3 Synthesis of compound 64-6

[0408] Intermediate 64-5 (3 g, 9.89 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (50 mL), and the nitrogen protection was replaced, then lithium aluminum hydride tetrahydrofuran solution (2.5 M, 3.96 mL, 1 eq) was slowly added to the system at 0 °C, and then stirred at 25 °C for 1 h. After TLC monitoring showed that the reaction was completed, the reaction solution was poured into 10 mL of water, then extracted with dichloromethane (10 mL x 3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 64-6 (300 mg, white-like gum).

[0409] Step 4 Synthesis of compound 64-7

[0410] Intermediate 64-6 (500 mg, 1.64 mmol, 1 eq) and reagent 64-a (2.23 g, 16.37 mmol, 10 eq) were dissolved in anhydrous dichloromethane (10 mL). A solution of boron trifluoride etherate (232.39 mg, 1.64 mmol, 201.38 μL, 1 eq) was added at 0 °C under nitrogen protection, then stirred at 5 °C for 8 h, and then stood at 5 °C for 16 h. After the reaction was monitored to completion by LCMS, saturated sodium bicarbonate (10 mL) was added to the reaction solution at 0 °C, dichloromethane (10 mL x 3) was added to extract the reaction solution, the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by reverse phase (formic acid system) to give intermediate 64-7 (60 mg, yield 8.65%, yellow oil).

[0411] Synthesis of compound 64

[0412] Intermediate 64-7 (50 mg, 118.07 μmol, 1 eq) was dissolved in tetrahydrofuran (3 mL) and hexafluoroisopropanol (3 mL), and the reaction solution was placed in a 10 mL metal coil. The metal coil was placed in a preheated 220 °C fluid chemical high-temperature reactor for 20 min, then removed and cooled to room temperature with water. The reaction was monitored to completion by LCMS, and concentrated under reduced pressure to give a crude product, which was purified by reverse phase separation (0.1% formic acid system and 15-45% acetonitrile) and lyophilized to give compound 64 (10 mg, formate, colorless oil, yield 22.75%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.50 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 1.6, 8.4 Hz, 1H), 6.76-6.75 (m, 1H), 4.61 (dd, J = 4.4, 8.4 Hz, 1H), 3.40 (m, 1H), 3.03-2.89 (m, 2H), 2.56 (s, 3H), 2.24-2.14 (m, 1H), 2.12-1.95 (m, 3H), 1.84-1.60 (m, 6H). LCMS: 324.1 [M+H] + .

[0413] Compound 67 was obtained by the same synthetic method as compound 64, and the characterization data of each compound are shown in the following table:

[0414] Example 22

[0415] Synthesis of compound 70-2

[0416] The starting material 70-1 (10 g, 57.08 mmol) was dissolved in acetonitrile (100 mL), and then pyridine (50 mL) and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (30.33 g, 85.62 mmol) were added in batches at 0 °C. The reaction solution was stirred at 20 °C for 1 h. After TLC detection showed that the reaction was complete, the reaction solution was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 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 / 0-3 / 1) to obtain intermediate 70-2 (4.6 g, white solid, yield 32.80%).

[0417] Synthesis of compound 70-3 in step 2

[0418] Intermediate 70-2 (2 g, 10.35 mmol) was dissolved in tetrahydrofuran (30 mL), and then sodium hydride (829 mg, 20.73 mmol, 60% purity) was added in batches at 0 °C under nitrogen protection. The reaction solution was stirred at 0 °C for 0.5 h. Then 2-(trimethylsilyl)ethoxymethyl chloride (2.24 g, 13.46 mmol) was added to the mixture at 0 °C under nitrogen protection, and the reaction solution was continuously stirred at 0 °C for 0.5 h. After LCMS detection showed that the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (40 mL) at 0 °C, and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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 = 10 / 1-5 / 1) to obtain intermediate 70-3 (2.5 g, yellow oil, yield 74.66%).

[0419] Synthesis of compound 70-4 in step 3

[0420] Morphinoline (1.36 g, 15.58 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), under nitrogen protection, 2-isobutylaluminum dihydride (1 M, 14.84 mL) was slowly added dropwise into the mixture at 0 °C, the reaction solution was stirred at 0 °C for 0.5 h, then the intermediate 70-3 (2.4 g, 7.42 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), slowly added dropwise into the reaction solution at -20 °C, after the addition was completed, it was stirred at -20 °C for 0.5 h. After the reaction was completed by LCMS detection, 1 M hydrochloric acid aqueous solution (30 mL) was added dropwise into the reaction solution at 0 °C, diluted with water (20 mL), then extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with brine (30 mL), then 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 = 10 / 1 ~ 5 / 1) to obtain the intermediate 70-4 (1.31 g, yellow oil, yield 60.11%).

[0421] Step 4 synthesis of compound 70-5

[0422] Potassium tert-butoxide (1.61 g, 14.38 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), under nitrogen protection, p-toluenesulfonylmethyl isocyanide (1.39 g, 7.14 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise into the mixture at -70 °C, the reaction solution was stirred at -70 °C for 15 min. Then under nitrogen protection, the intermediate 70-4 (1.31 g, 4.46 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise into the mixture at -70 °C, the reaction solution was stirred at -70 °C for 1.5 h. Then anhydrous methanol (40 mL) was added into the reaction solution, the reaction solution was stirred at 60 °C for 0.5 h. After the reaction was completed by TLC detection, the reaction solution was concentrated under reduced pressure to obtain a residue, diluted with water (30 mL), then extracted with ethyl acetate (40 mL x 3), the combined organic phase was 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 column (C18 column, 0.1% formic acid system and 70-80% acetonitrile), the fraction was adjusted to pH 9 with saturated sodium bicarbonate solution, concentrated under reduced pressure to remove acetonitrile, the residue was extracted with ethyl acetate (40 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the intermediate 70-5 (1.03 g, yellow oil, yield 75.78%).

[0423] Step 5 synthesis of compound 70-6

[0424] Intermediate 70-5 (1.03 g, 3.38 mmol) was dissolved in ethanol (15 mL), 5M aqueous potassium hydroxide solution (5M, 14.89 mL) was added into the mixture, the reaction solution was stirred at 90°C for 12 hours. After TLC detection reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue, the pH was adjusted to 3 with 1M aqueous hydrochloric acid solution at 0°C, then extracted with ethyl acetate (30 mL x 3), the combined organic phase was 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 = 5 / 1~3 / 1) to obtain intermediate 70-6 (1.04 g, yellow oil, yield 95.04%).

[0425] Step 6 synthesis of compound 70-7

[0426] Intermediate 70-6 (1 g, 3.09 mmol) and dimethylamine hydrochloride (350.00 mg, 4.29 mmol) were dissolved in anhydrous dichloromethane (20 mL), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (750.00 mg, 3.91 mmol) and DMAP (38 mg, 311.04 μmol) were added into the mixture under nitrogen protection at 0°C, the reaction solution was stirred at 0°C for 10 minutes, then N,N-diisopropyl ethylamine (1.25 g, 9.67 mmol) was slowly added into the reaction solution at 0°C, the reaction solution was stirred at 20°C for 12 hours. After LCMS detection reaction was completed, the reaction solution was concentrated to obtain a residue, the residue was diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was freeze-dried by reversed-phase chromatography column (C18 column, 0.05% ammonia system and 37-67% acetonitrile) to obtain intermediate 70-7 (390 mg, white solid, yield 35.99%).

[0427] Step 7 synthesis of compound 70-8

[0428] Intermediate 70-7 (331 mg, 944.36 μmol) was dissolved in anhydrous tetrahydrofuran (12 mL), under the protection of nitrogen, lithium bis(trimethylsilyl)amide (1 M, 1.42 mL) was slowly added dropwise into the mixture at -70 °C, the reaction solution was stirred at -70 °C for 0.5 h, then cyclohexanone (149 mg, 1.52 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), slowly added dropwise into the reaction solution at -70 °C, after the addition was completed, it was stirred at -70 °C for 0.5 h. After the reaction was completed by LCMS detection, 1 M aqueous hydrochloric acid (2.2 mL) was added dropwise into the reaction solution at 0 °C, diluted with water (20 mL), then extracted with ethyl acetate (30 mL x 3), the organic phase was washed with brine (30 mL), then 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 = 10 / 1 ~ 5 / 1) to obtain intermediate 70-8 (420 mg, yellow oil, yield 99.13%).

[0429] Synthesis of compound 70-9 in step 8

[0430] Aluminum trichloride (135 mg, 1.01 mmol) was suspended in tetrahydrofuran (15 mL), under the protection of nitrogen, lithium aluminum hydride (2.5 M, 1.13 mL) was slowly added dropwise into the reaction solution at 0 °C, after the addition was completed, it was stirred at 0 °C for 15 min. Then intermediate 70-8 (420 mg, 936.16 μmol) was dissolved in tetrahydrofuran (5 mL), slowly added dropwise into the reaction solution at 0 °C under the protection of nitrogen, the reaction solution was stirred at 10 °C for 0.5 h. After the reaction was completed by LCMS detection, 0.17 mL of water, 0.17 mL of 15% aqueous sodium hydroxide solution and 0.51 mL of water were sequentially added dropwise into the reaction solution at 0 °C to quench the reaction, then dried over anhydrous sodium sulfate, filtered, the filter cake was washed with dichloromethane (20 mL x 3), the filtrate was collected and concentrated under reduced pressure to obtain intermediate 70-9 (402 mg, yellow oil, yield 98.79%).

[0431] Synthesis of compound 70 in step 9

[0432] Intermediate 70-9 (402 mg, 924.86 pmol) was dissolved in tetrahydrofuran (10 mL), then tetra butyl ammonium fluoride (1 M, 9.25 mL) was added to the mixture. The reaction was stirred at 50 °C for 8 h. Tetramethylethylenediamine (2.15 g, 18.50 mmol) was added to the mixture, and the reaction was stirred at 70 °C for 24 h. After LCMS detection of the completion of the reaction, the reaction was poured into saturated ammonium chloride (30 mL), diluted with water (20 mL), and then extracted with ethyl acetate (40 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase chromatography (C18 column, 0.1% formic acid system and 18-25% acetonitrile). Compound 70 (280 mg, yellow solid, yield 99.46%) was obtained after lyophilization.

[0433] Step 10 synthesis of compound 70A / 70B

[0434] Compound 70 (280 mg, 919.84 pmol) was purified by SFC chiral separation (column type: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 18%, isocratic elution mode) to give 70A (retention time: 1.430 min, 66.38 mg, purple solid, yield 23.68%), 1 H NMR (400 MHz, DMSO-d6) d = 10.73 (br s, 1H), 8.25 (s, 1H), 7.35 (s, 1H), 7.29-7.19 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 3.23 (dd, J = 7.2, 12.8 Hz, 1H), 2.96 (t, J = 7.2 Hz, 1H), 2.77 (dd, J = 8.0, 12.8 Hz, 1H), 2.28 (s, 6H), 1.66-0.83 (m, 10H). LCMS: 305.2 [M+H] + and 70B (retention time: 1.535 min, 77.71 mg, off-white solid, yield 27.75%), 1 H NMR (400 MHz, DMSO-d6) d = 10.73 (br s, 1H), 8.25 (s, 1H), 7.35 (s, 1H), 7.29-7.19 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 3.23 (dd, J = 7.2, 12.8 Hz, 1H), 2.96 (t, J = 7.2 Hz, 1H), 2.77 (dd, J = 8.0, 12.8 Hz, 1H), 2.28 (s, 6H), 1.66-0.83 (m, 10H). LCMS: 305.2 [M+H]+ .

[0435] Example 23

[0436] Synthesis of compound 71-2

[0437] The starting material 71-1 (3 g, 14.08 mmol, 1 eq) was dissolved in tetrahydrofuran (90 mL), then trimethylsilyl chloride (3.57 mL, 28.16 mmol, 2 eq) was added, and then nitrogen was replaced, and lithium diisopropylamide (2 M, 7.74 mL, 1.1 eq) was added dropwise at -78 °C, and then the reaction was stirred at -78 °C for 1.5 hours. After TLC detection of the complete reaction, the reaction solution was added dropwise to saturated ammonium chloride aqueous solution (150 mL) at 0 °C under nitrogen protection to quench the reaction. After quenching, 50 mL of water was added for dilution, and then the aqueous phase was extracted with ethyl acetate (150 mL x 3), and the combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 - 10 / 1) to obtain intermediate 71-2 (3.95 g, colorless oil, yield 93.43%).

[0438] Synthesis of compound 71-3

[0439] Intermediate 71-2 (3.13 g, 10.96 mmol, 1 eq) was dissolved in DMF (95 mL), then N-chlorosuccinimide (1.68 g, 12.60 mmol, 1.15 eq) was added, and then nitrogen was replaced, and the reaction solution was slowly warmed to 75 °C for 3 hours. After TLC detection of the complete reaction, the reaction solution was added to water (100 mL) at room temperature, and the aqueous phase was extracted with ethyl acetate (75 mL x 3), and then the combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 - 10 / 1) to obtain intermediate 71-3 (3.35 g, yellow solid, yield 90.87%).

[0440] Synthesis of compound 71-4

[0441] After intermediate 71-3 (3.35 g, 10.48 mmol, 1 eq) was dissolved in tetrahydrofuran (67 mL), a solution of tetrabutylammonium fluoride (1 M, 11.53 mL, 1.1 eq) was added, and the reaction solution was reacted at 25 °C for 3 h. After TLC detection showed that the reaction was complete, the reaction solution was added to water (100 mL) at room temperature, the aqueous phase was extracted with ethyl acetate (75 mL x 3), the combined organic phase was washed with 1 M dilute hydrochloric acid (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0-10 / 1) to obtain intermediate 71-4 (2.32 g, yellow solid, yield 80.68%).

[0442] Synthesis of compound 71-6 in step 4

[0443] After intermediate 71-4 (2 g, 8.08 mmol, 1 eq) was dissolved in DMF (60 mL), raw material 71-5 (4.57 g, 24.24 mmol, 5.29 mL, 3 eq), zinc fluoride (2.51 g, 24.24 mmol, 3 eq), and methanesulfonic acid (tri-tert-butyl phosphine) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (466.81 mg, 816.03 μmol, 1.01e-1 eq) were added, and then nitrogen was replaced, and the reaction solution was reacted at 100 °C for 12 h. After TLC detection showed that the reaction was complete, the reaction solution was filtered with diatomite. Water (100 mL) was added to the filtrate, and then the aqueous phase was extracted with ethyl acetate (75 mL x 3), and then the combined organic phase was washed with saturated brine (150 mL), and the combined organic phase was 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 / 0-10 / 1) to obtain intermediate 71-6 (1.55 g, light yellow oil, yield 63.76%).

[0444] Synthesis of compound 71-7 in step 5

[0445] After intermediate 71-6 (1.55 g, 6.44 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), potassium trimethylsilanolate (1.65 g, 12.88 mmol, 2 eq) was added, and the reaction solution was reacted at 25 °C for 1 h. After TLC detection showed that the raw material was completely reacted, 1 N aqueous hydrochloric acid was added dropwise to the reaction solution to adjust the pH to about 3, the aqueous phase was extracted with ethyl acetate (30 mL) three times, and then the combined organic phase was washed with saturated brine (80 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 = 5 / 1-3 / 1) to obtain intermediate 71-7 (1.2 g, white solid, yield 65.77%).

[0446] Step 6. Synthesis of compound 71-8

[0447] After intermediate 71-7 (1.18 g, 5.21 mmol, 1 eq) and dimethylamine hydrochloride (509.38 mg, 6.25 mmol, 572.34 μL, 1.2 eq) were dissolved in dichloromethane (25 mL), the solution was cooled to 0 °C, diisopropylethylamine (3.36 g, 26.03 mmol, 4.53 mL, 5 eq) and 1-butylphosphonic anhydride (4.50 g, 6.25 mmol, 50% purity, 1.2 eq) were added under nitrogen protection, and the reaction solution was slowly warmed to 20 °C for 1 h. After the reaction was completed by LCMS detection, the reaction solution was added to water (30 mL) at room temperature, the aqueous phase was extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by reverse phase chromatography (C18 column, 0.1% formic acid system and 40-55% acetonitrile) to give intermediate 71-8 (600 mg, light brown solid, yield 42.06%).

[0448] Step 7. Synthesis of compound 71-9

[0449] After intermediate 71-8 (580 mg, 2.29 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (12 mL) and the nitrogen was replaced, lithium bis(trimethylsilyl)amide (1 M, 3.43 mL, 1.5 eq) was added dropwise at -70 °C, and the reaction solution was stirred at -70 °C for 30 min. Cyclohexanone (448.66 mg, 4.57 mmol, 473.77 μL, 2 eq) was dissolved in anhydrous tetrahydrofuran (3 mL) and added dropwise to the reaction solution under nitrogen protection at -70 °C, and the reaction solution was stirred at -70 °C for 30 min. After the reaction was completed by TLC detection, the reaction was quenched by adding 1 N aqueous hydrochloric acid (12 mL) dropwise to the reaction solution at below -40 °C, and then 30 mL of water was added to dilute the solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1 - 3 / 1) to give intermediate 71-9 (750 mg, colorless gum, yield 74.60%).

[0450] Step 8. Synthesis of compounds 71A / 71B

[0451] After dissolving aluminum trichloride (302.38 mg, 2.27 mmol, 123.93 μL, 1.14 eq) in tetrahydrofuran (14 mL), lithium aluminum hydride (2.5 M, 2.39 mL, 3 eq) was slowly added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 0 °C for 15 min, then a tetrahydrofuran (7 mL) solution of intermediate 7-9 (700 mg, 1.99 mmol, 1 eq) was added. After the addition was completed, the reaction was continued at 0 °C for half an hour. After the reaction was completed by LCMS monitoring, the reaction solution was first diluted with 20 mL of tetrahydrofuran, then 0.5 mL of water, 0.5 mL of 15% sodium hydroxide aqueous solution, 1.5 mL of water and anhydrous sodium sulfate were slowly added dropwise to the reaction solution under ice bath conditions. Filtration, collection of the filtrate, and concentration of the filtrate under reduced pressure gave the crude product compound 71. The crude product was purified by SFC separation method (column type: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) to give 71A (retention time: 1.568 min, 172.99 mg, white gum) and 71B (retention time: 1.791 min, 210.74 mg, white solid), 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.41 (dd, J = 1.2, 8.4 Hz, 1H), 3.06 - 2.94 (m, 2H), 2.79 (dd, J = 8.4, 12.0 Hz, 1H), 2.17 (s, 6H), 1.68 - 1.60 (m, 1H), 1.59 - 1.51 (m, 1H), 1.50 - 1.31 (m, 4H), 1.28 - 1.21 (m, 1H), 1.21 - 1.08 (m, 2H), 1.05 - 0.95 (m, 1H). LCMS: 338.1 [M+H] + and 71B (retention time: 1.791 min, 210.74 mg, white solid), 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.41 (dd, J = 1.2, 8.4 Hz, 1H), 3.06 - 2.94 (m, 2H), 2.79 (dd, J = 8.4, 12.0 Hz, 1H), 2.17 (s, 6H), 1.68 - 1.60 (m, 1H), 1.59 - 1.51 (m, 1H), 1.50 - 1.31 (m, 4H), 1.28 - 1.21 (m, 1H), 1.21 - 1.08 (m, 2H), 1.05 - 0.95 (m, 1H). LCMS: 338.1 [M+H]+ .

[0452] Test Example 1. Test for monoamine reuptake inhibition

[0453] 1. Test material: Monoamine Neurotransmitter Assay Kit (Molecular devices, Cat# R8174)

[0454] G418 (Invitrogen Cat# 10131-027)

[0455] Automated liquid handling platform Bravo, Agilent

[0456] Detection instrument Perkin Elemer EnVision

[0457] 2. Test method:

[0458] a. HEK293 cells expressing recombinant human dopamine, norepinephrine and serotonin transporters, respectively, were used to analyze the inhibition of human monoamine reuptake transporters using the above stable cell lines. The reference compounds used were BTCP, Nisoxetine hydrobromide, Citalopram hydrobromide, respectively.

[0459] b. Cells were thawed and passaged twice. The cell suspension was diluted to 1 x 10 6 cells / mL (20000 cells per 20 μL well) using culture medium and seeded into 384-well cell plates.

[0460] c. The reference compounds and test compounds were prepared in assay buffer (20 mM HEPES in HBSS, containing 0.1% BSA) with a maximum test concentration of 10 μM in 4-fold serial dilutions. 25 μL / well of compound dilutions were transferred to the 384-well cell plates by Bravo. For the high control wells, 25 μL of 0.25% dimethyl sulfoxide was added. For the low control group, 25 μL of 1 μM reference compound solution was added.

[0461] d. Centrifugation at 300 rpm for 15 s, followed by incubation at 37°C for 30 min.

[0462] e. After incubation with the compounds, 25 μL of dye solution was added per well. Incubation at 37°C for 60 min.

[0463] f. The test plates were read on the EnVision. The test results were analyzed using XLFIT5 software.

[0464] g.Test results: the inhibitory effect of the compound of the present application on monoamine reuptake is shown in Table 1. Among them, A represents: IC 50 <10nM; B represents: 10nM≤IC 50 <100nM; C represents: 100nM≤IC 50 <1000nM; D represents: 1000nM≤IC 50 <10000nM; E represents: IC 50 >10000nM. At an average inhibition of 10μM, * represents: 0-50% inhibition; ** represents: 51-100% inhibition.

[0465] Table 1 Test results of monoamine reuptake inhibition

[0466] Test Example 2. Functional test of the compound on S1R receptor

[0467] 1. Experimental materials:

[0468] PRE-084 (MCE, Cat# HY-18100A)

[0469] BD-1047 (MCE, Cat# HY-16996A)

[0470] Plasmid pCDH-σ1R-LgBiT-P2A-signalP-SmBiT-BiP-T2A-BSD (self-made)

[0471] Lipofectamine 2000 Reagent (invitrogen, Cat# 2856194)

[0472] Furimazine (PBI 3939)

[0473] Multifunctional enzyme label instrument (BioTeK Synergy H1)

[0474] 2. Test method: using a new type of nanofluorescein doublet technology (NanoBiT)

[0475] (1) Construct pCDH-σ1R-LgBiT-P2A-signalP-SmBiT-BiP-T2A-BSD plasmid.

[0476] (2) 293T cells are resuscitated and subcultured more than twice. The cell suspension is diluted with culture medium and inoculated into a 96-well cell plate at a density of 14000 / well for 22h of culture.

[0477] (3) Transfect plasmid (400 ng) with Lipofectamine 2000 Reagent reagent, incubate for 6 h, and then replace with complete medium.

[0478] (4) Dilute the test compound with medium and add to the cell-containing 96-well plate, so that the highest test concentration is 10 μM, 3-fold gradient dilution, a total of 10 test concentrations. 5% DMSO as a blank control group. Incubate for 24 h.

[0479] (5) Add 10 μM luminescent substrate Furimazine and act for 10 min, and use an enzyme marker to read the luminescence value.

[0480] (6) According to the RLU (-%ΔBasal) value at different concentrations, calculate the EC 50 of the compound to SIR.

[0481] 3. Test results:

[0482] The relative fluorescence of the compound 16-B-2, 24A treatment group is significantly reduced compared with the control group, and it is judged that the compound 16-B-2, 24A is an agonist. As shown in Table 2, the EC 50 range is 0-100 nM, 100-1000 nM, respectively.

[0483] Table 2 Test results of sigma-1R agonistic activity

[0484] 4. Test conclusion

[0485] The compound 16-B-2, 24A of the application is a sigma-1 receptor agonist.

[0486] Test example 3. Affinity test of the compound to S1R receptor

[0487] 1. Experimental materials

[0488] Microscint 20 cocktail (PerkinElmer, Cat#6013329)

[0489] PEI (Poly ethyleneimine) (Sigma, Cat#P3143)

[0490] Tris base (Sigma, Cat#T1503-1KG)

[0491] Unifilter-96 GF / C filter plates (Perkin Elmer, Cat#6005174)

[0492] 96 well conical polypropylene plates (Agilent, Cat# 5042-1385)

[0493] TopSeal-A sealing film (Perkin Elmer, Cat# 6050185)

[0494] MicroBeta2 (Perkin Elmer)

[0495] 2. Experimental method

[0496] a) Collect stable transfected sigma-1R HEK293 cells, homogenize and use 50000g ultracentrifugation. The precipitate is diluted with 50mM Tris-HCl (pH 7.4) to a concentration of 1.95mg / mL.

[0497] b) Dilute the compound with 50mM Tris-HCl (pH 7.4). The reference compound is haloperidol, the highest test concentration of the test compound is 10μM, 3-fold concentration dilution, 8 concentration points. Select 3 H]DTG as the radioactive ligand, with a final concentration of 5nM.

[0498] c) Use Multi-pipette to transfer the sequentially diluted reference compound and test to the test plate. Use haloperidol with a highest concentration of 10μM as Low control, and use 0.5% DMSO as High control.

[0499] d) Add 100μL membrane solution to the test plate, with a final concentration of 8μg / well. Then add 100μL radioactive ligand, seal the plate and mix well at a speed of 300rpm.

[0500] e) Soak the Unifilter-96 GF / C filter plate with 50μL 0.3% PEI per well at room temperature for at least 0.5 hours.

[0501] f) After the completion of the binding experiment, use Perkin-Elmer Filtermate Harvester to filter the reaction mixture through the GF / C plate, and then wash it with pre-cooled washing buffer (50mM Tris-HCl pH7.4) for 6 times.

[0502] g) After drying at 50°C, the bottom of the filter plate well was sealed using Perkin-Elmer Unifilter-96 backing seal tape. 50 μL of Perkin-Elmer Microscint 20 cocktail was added, and the top of the filter plate was sealed using Perkin-Elmer TopSeal-A sealing film.

[0503] h) The adsorbed radioactivity on the filter plate was counted using a Perkin-Elmer MicroBeta2 Reader. 3 H.

[0504] i) The inhibition rate was calculated using the following equation: % Inhibition = (1-(Assay well-Average_LC) / (Average_HC-Average_LC))*100%.

[0505] j) The data was analyzed using the "log(inhibitor) vs. response - Variable slope" model of Graphpad Prism 5. Where A represents: %Inh≤20%; B represents: 20%< %Inh≤40%; C represents: 40%< %Inh≤60%; D represents: 60%< %Inh≤80%; E represents %Inh>80%.

[0506] 3. Test results:

[0507] Table 3 Monoamine reuptake inhibition test results

[0508] 4. Test conclusion: The compounds 3A, 4A, 24A, 28-A, 29A, 30A, 31A, 70A, 71A, 71B of the present application have affinity with sigma-1 receptor.

[0509] Test Example 4. Effect of compounds on hyperactivity of SHR model rats

[0510] 1. Experimental materials

[0511] SHR rats (Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0512] Normal saline (Shandong Kelun Pharmaceutical Co., Ltd. B24090204A)

[0513] VisuTrack animal behavior analysis software and open field rat test equipment (Shanghai Xinsuo Information Technology Co., Ltd.)

[0514] 2. Experimental method

[0515] a) Male SHR rats (100-120 g) were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (No. 110011241110079263) and maintained on a 12 / 12 light / dark cycle at room temperature between 20-23℃ and relative humidity of 50%.

[0516] b) 3A was prepared with DMSO: 15% SBECD (5%:95%) to make the concentration 3 mg / mL. Compound 24A was dissolved with normal saline to make the concentration 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, respectively.

[0517] c) Intragastric administration, the administration volume of 24A was 10 mL / kg, i.e. the administration concentration was 0.5 mg / kg, 1 mg / kg, 2 mg / kg (6-7 rats in each group).

[0518] d) Intragastric administration, the administration volume of 3A was 5 mL / kg, i.e. the administration concentration was 15 mg / kg (5 rats in each group).

[0519] e) After administration, the rats were placed in the open field test box, and the horizontal activity distance of the rats within 60 min after administration was recorded and analyzed using VisuTrack animal behavior analysis software.

[0520] 3. Experimental results: As shown in Figures 1-4, administration of compounds 3A and 24A can significantly reduce the horizontal activity distance of rats within 30 min and 60 min after administration. *p<0.05; **p<0.01; ***p<0.001 vs SHR group.

Claims

1. A compound represented by Formula (II), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof: wherein R1is selected from: R 1a and R 1b are each independently selected from the group consisting of: H, or C 1-6 alkyl; m is selected from 0, 1, 2, or 3; R 2a and R 2b together with the carbon atom to which they are attached form a ring X 2a and one of X 2c is selected from: NR4, N, O, or S, 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 a single or double bond; provided that when X 2a and / or X 2c is O or S, X 2a and / or X 2c is connected to is selected from a single bond; each occurrence of R4is independently selected from: H, halo, or C 1-6 alkyl; Y2is 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; R3is selected from: R 3a selected from: H, halogen, or OH; R 3b selected from: C 3-10 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl, said C 3-10 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl, optionally substituted with one or more R6; R 3c selected from: H, or OH; X 3a , X 3b , X 3c , X 3d , X 3e are each 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 one of the groups forms a C3-6cycloalkyl, the others being C(R7)2; R 5a and R 5b each independently is selected from H, halogen, or OH; R6is each independently selected from: H, halo, C 1-6 alkyl, or C 1-6 alkoxy; R7is each independently selected from: H, halo, C 1-6 alkyl, or C 1-6 alkoxy.

2. The compound, pharmaceutically acceptable salt, stereoisomer, or deuterated form of claim 1, wherein: The compounds have a structure as formula (IIA) or (IIB): wherein 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 , Y2, and m are as defined in claim 1.

3. The compound, pharmaceutically acceptable salt, stereoisomer, or deuterated form of claim 1, wherein: The compounds have a structure according to Formula (IIC) or (IID): wherein R1is selected from: R 1a and R 1b are each independently selected from the group consisting of: H, or C 1-6 alkyl; m is selected from 0, 1, 2, or 3; Y2is 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 are each independently selected from the group consisting of H, halogen, or C 1-6 alkyl; R 3b selected from: C 3-10 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl, said C 3-10 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl optionally substituted with one or more R6; R 5b selected from: H, halogen, or OH; R6is selected from: H, halo, C 1-6 alkyl, or C 1-6 alkoxy.

4. The compound, pharmaceutically acceptable salt, stereoisomer, or deuterated form of claim 3, wherein: The compounds have a structure according to Formula (IIC-1), (IIC-2), (IID-1), or (IID-2): wherein R1, R 1a , R 1b , R 2c , R 2d , R 3b , R 4a , R 4b , R 4c , R 5b , R6, X 2a , Y2, and m are as defined in claim 3.

5. The compound, pharmaceutically acceptable salt, stereoisomer, deuterated isomer thereof of any one of claims 1-4, wherein, R1is selected from: R 1a and R 1b each independently selected from: H, methyl, ethyl, n-propyl, i-propyl; m is selected from 0, 1, 2, or 3.

6. The compound, pharmaceutically acceptable salt, stereoisomer, deuterated form of any one of claims 1, 2, or 5, wherein R 2a and R 2b together with the carbon atom to which they are attached form a ring The ring selected from the group consisting of each R 4a , R 4b , R 4c , each independently when present, is selected from: H, halo, or C 1-6 alkyl.

7. The compound, pharmaceutically acceptable salt, stereoisomer, deuterated form of any one of claims 1-6, wherein each R 4a , R 4b , R 4c is independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 2c and R 2d are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or i-propyl; R 5a and R 5b are each independently selected from H, F, CI, Br, I, OH, or R 5a , R 5b and the carbon atom to which they are attached together form a cyclopropyl group.

8. The compound, pharmaceutically acceptable salt, stereoisomer, deuterated isomer thereof of any one of claims 1-7, wherein, R3is selected from: R 3a selected from: OH; R 3b selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl is optionally substituted with one or more (e.g.: 1, 2, 3, 4, 5) R6; R6is selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, or i-propoxy.

9. The compound, pharmaceutically acceptable salt, stereoisomer, deuterated form of any one of claims 1-8, wherein, R3is selected from: R 3c selected from: H, or OH; X 3a , X 3b , X 3c , X 3d , X 3e any one of X 3a , X 3b , X 3c , X 3d , X 3e are all selected from C(R7)2, or X 3a , X 3b , X 3d , X 3e are all selected from CH2, X 3c is selected from C(R7)2, or X 3a and X 3b form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, X 3c , X 3d , X 3e is selected from C(R7)2; R7is each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, or i-propoxy.

10. The compound of claims 1-9, pharmaceutically acceptable salts, stereoisomers, deuterated forms thereof, having the structure:

11. The compound of any one of claims 1-10, pharmaceutically acceptable salts, stereoisomers, deuterated forms thereof, having the structure:

12. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, stereoisomer, or deuterated form of any one of claims 1-11 and a pharmaceutically acceptable carrier.

13. Use of a compound, pharmaceutically acceptable salt, stereoisomer, deuterated form of any one of claims 1-11 or a pharmaceutical composition of claim 12 in the manufacture of a medicament.

14. The use of claim 13, wherein the medicament is for the prevention, treatment, or amelioration of a dopamine, norepinephrine, and / or serotonin, and / or Sigma-1 receptor mediated related disease in a patient.

15. The use of claim 13, wherein the medicament is for the prevention, treatment, or amelioration of a CNS disorder, CNS disease, and / or one or more related symptoms thereof in a patient.

16. The use of claim 13, wherein the medicament is for the improvement and / or promotion of neuroprotection, neurogenesis in a patient.

17. The use of claim 14 or 15, wherein the dopamine, norepinephrine, serotonin, and / or Sigma- 1 receptor mediated related disease, CNS disorder, CNS disease, and / or one or more related symptoms thereof comprise: Attention Deficit Disorder / Attention Deficit Hyperactivity Syndrome (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, drug 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 propensity, nicotine abuse, tobacco abuse, cocaine abuse, alcohol addiction, sexual dysfunction, osteoporosis, menopausal symptoms, metabolism and eating disorders, spinal cord lateral sclerosis, stroke, regulation of bone metabolism, etc.

Images