A benzene ring-containing compound having analgesic efficacy and a preparation method and use thereof

Abstract

The application relates to a benzene ring-containing compound with analgesic efficacy, a preparation method and use thereof, and relates to the field of medicinal chemistry. The compound is a compound shown in formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium derivative thereof. The analgesic effect of the compound is excellent, the compound is safe to use, has small toxic and side effects, and does not produce dependence during use. Therefore, the compound has a wide application prospect in the preparation of analgesic drugs, and provides a new selection for preparing drugs with analgesic action in the clinic.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a compound containing a benzene ring that has analgesic effects, its preparation method, and its uses. Background Technology

[0002] The Global Burden of Disease Study reports that pain and pain-related disorders are a leading cause of disability and disease burden globally. The report shows that over 80% of patients undergoing surgery experience acute postoperative pain, less than half achieve adequate pain relief, and nearly 80% of these patients have moderate to severe pain scores. Furthermore, 10% to 50% of patients experience chronic postoperative pain. Therefore, there remains a significant clinical need for analgesics. In the field of pain management, traditional opioids remain the most effective and commonly used analgesics for moderate to severe pain. Opioids exert their analgesic effect by acting on opioid receptors in the G protein-coupled receptor family, primarily activating the downstream Gi / o protein pathway.

[0003] However, while opioids provide potent analgesia, they also come with numerous adverse reactions. These include common respiratory depression, deep sedation, nausea, vomiting, and constipation. Long-term use can lead to tolerance, decreased pain perception, and even drug abuse and addiction, causing serious social harm. Opioids that act on μ-receptors can produce dose-dependent respiratory depression through direct action on the brainstem respiratory center. Studies have shown that the addiction rate of opioids averages between 8% and 12%. Patients with physical dependence or addiction to opioids often abuse them to avoid withdrawal symptoms.

[0004] Although researchers have developed many novel opioid and even non-opioid analgesics over the past century, no particularly significant progress has been made. For example, Olicaeridine (TRV130), a μ-receptor-targeting analgesic designed based on the G protein bias concept, was approved by the US Food and Drug Administration (FDA) in 2020 for the treatment of moderate to severe pain, but it still carries a "black box warning" emphasizing its continued opioid-related side effects. Many known analgesics targeting other non-opioid receptors have not yet achieved analgesic effects comparable to morphine or remifentanil, or have failed to produce results consistent with animal studies in multiple clinical trials, due to limitations in the analgesic targets or pain models.

[0005] In conclusion, while traditional opioids are the most effective drugs for treating moderate to severe pain, their adverse reactions and drug dependence limit their effectiveness. Furthermore, they reduce safety and lead to serious social problems such as drug abuse. Therefore, designing a novel non-opioid analgesic that retains the analgesic efficacy of opioids while avoiding their serious adverse reactions is of great clinical significance and has broad market prospects. Summary of the Invention

[0006] The purpose of this invention is to provide a compound containing a benzene ring with analgesic effects, its preparation method, and its uses.

[0007] This invention provides compounds of Formula I, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their crystal forms, or their prodrugs, or their metabolites, or their deuterated derivatives:

[0008]

[0009] in,

[0010] R1 and R4 are independently selected from hydrogen or NR6R7, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, substituted or unsubstituted C1-C6 alkyl, OR 1a R 1a It is selected from C1 to C6 alkyl, 5 to 8 aryl, and 5 to 8 heteroaryl, and only one of R1 and R4 is selected from NR6R7;

[0011] R2, R3, and R5 are each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, NR6R7, and (CH2), respectively. p CONHR 1b , halogens, hydroxyl groups; p is selected from integers from 0 to 5, R 1b Selected from C1-C6 alkyl, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl;

[0012] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0013] m is selected from integers from 0 to 5; n is selected from integers from 0 to 5;

[0014] X1 and X2 are independently selected from O, S, and NR8, respectively;

[0015] Each R8 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0016] L is selected from C=X3, substituted or unsubstituted 4-8 membered cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl;

[0017] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0018] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0019] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0020] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0021] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-8 heteroaryl groups and 5-8 aryl groups.

[0022] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0023] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =O;

[0024] The heterocyclic alkyl and heteroaryl groups have heteroatoms of O, S and / or N, and the number of heteroatoms is 1 to 5.

[0025] When ring A is When X1 and X2 are both NH, L is C=O, m is 0, and n is 1. Not for

[0026] When ring A is When X1 and X2 are both NH, L is C=O, and m and n are 0. Not for

[0027] When ring A is When X1 and X2 are both NH, L is C=NH, m is 1, and n is 2. Not for

[0028] Furthermore, the compound is of formula IIa or IIb:

[0029]

[0030] in,

[0031] R2 and R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, NR6R7, and (CH2), respectively. p CONHR 1b , halogens, hydroxyl groups; p is selected from integers from 0 to 5, R 1b Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0032] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, halogens, and hydroxyl groups;

[0033] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0034] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0035] X1 and X2 are independently selected from O, S, and NR8, respectively;

[0036] Each R8 is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0037] L is selected from C=X3, substituted or unsubstituted 4-8 membered cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl;

[0038] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0039] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0040] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0041] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0042] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-8 heteroaryl groups and 5-8 aryl groups.

[0043] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0044] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =O;

[0045] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0046] Furthermore, the compound is of formula IIIa or IIIb:

[0047]

[0048] in,

[0049] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, halogens, and hydroxyl groups;

[0050] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0051] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0052] X1 and X2 are independently selected from O, S, and NR8, respectively;

[0053] Each R8 is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0054] L is selected from C=X3, substituted or unsubstituted 4-8 membered cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl;

[0055] X3 is selected from O, S, NR9, and CR. 10R 11 ;

[0056] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0057] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0058] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0059] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-8 heteroaryl groups and 5-8 aryl groups.

[0060] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0061] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =O;

[0062] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0063] Furthermore,

[0064] X1 and X2 are independently selected from O, S, and NH, respectively;

[0065] And / or, L is selected from

[0066] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0067] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0068] R 10 R 11Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0069] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0070] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0071] Furthermore,

[0072] Selected from

[0073] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0074] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0075] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0076] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0077] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0078] Furthermore, the compound is as shown in Formula IV:

[0079]

[0080] in,

[0081] R1 and R4 are independently selected from hydrogen or NR6R7, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, substituted or unsubstituted C1-C6 alkyl, OR 1a R 1a It is selected from C1 to C6 alkyl or phenyl, and only one of R1 and R4 is selected from NR6R7;

[0082] R2, R3, and R5 are each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, NR6R7, and (CH2), respectively. p CONHR 1b , halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-5 membered cycloalkyl, and 3-5 membered heterocycloalkyl;

[0083] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0084] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0085] X1 and X2 are independently selected from O, S, and NR8, respectively;

[0086] Each R8 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0087] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0088] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0089] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0090] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0091] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-8 heteroaryl groups and 5-8 aryl groups.

[0092] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0093] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy groups.

[0094] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0095] Furthermore, the compound is of formula IVa:

[0096]

[0097] in,

[0098] R1 and R4 are independently selected from hydrogen or NR6R7, 3-4 membered cycloalkyl, 3-4 membered heterocycloalkyl, substituted or unsubstituted C1-C6 alkyl, OR 1a R 1a It is selected from C1 to C6 alkyl or phenyl, and only one of R1 and R4 is selected from NR6R7;

[0099] R2, R3, and R5 are each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, NR6R7, and (CH2), respectively. p CONHR 1b Halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-4 membered cycloalkyl, and 3-4 membered heterocycloalkyl;

[0100] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0101] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0102] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-6 heteroaryl groups, and 6 aryl groups.

[0103] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0104] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy groups.

[0105] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0106] Furthermore, the compound is of formula Va or Vb:

[0107]

[0108] in,

[0109] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, NR6R7, and (CH2). p CONHR 1b , halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-4 membered cycloalkyl, and 3-4 membered heterocycloalkyl;

[0110] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0111] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0112] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0113] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0114] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0115] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0116] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-6 heteroaryl groups, and 6 aryl groups.

[0117] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0118] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy groups.

[0119] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0120] Furthermore, the compound is of formula VIa or VIb:

[0121]

[0122] in,

[0123] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, NR6R7, and (CH2). p CONHR 1b , halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-4 membered cycloalkyl, and 3-4 membered heterocycloalkyl;

[0124] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0125] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0126] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0127] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R 12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0128] R12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0129] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-6 heteroaryl groups, and 6 aryl groups.

[0130] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0131] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy groups.

[0132] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0133] Furthermore, the compound is of formula VIIa or VIIb:

[0134]

[0135] in,

[0136] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, and (CH2). p CONHR 1b Halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-4 membered cycloalkyl, and 3-4 membered heterocycloalkyl;

[0137] R6 and R7 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0138] X3 is selected from O, S, NR9, and CR. 10 R 11 ;

[0139] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0140] R 10 R 11 Each group is independently selected from hydrogen, cyano, nitro, and -C(O)R12 substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups;

[0141] R 12 Selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups;

[0142] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, substituted or unsubstituted 5-8 heteroalkyl groups, substituted or unsubstituted 5-6 heteroaryl groups, and 6 aryl groups.

[0143] The number of substituents of the alkyl or alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0144] The number of substituents in the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy groups.

[0145] The heterocyclic alkyl or heteroaryl groups contain heteroatoms of O, S, and / or N, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0146] Furthermore,

[0147] Ring A is selected from the following groups, whether substituted or unsubstituted:

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] The substituents of ring A are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, C1-C6 alkyl, and C1-C6 alkoxy.

[0157] Preferably, the substituents of ring A are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, C1-C4 alkyl, and C1-C4 alkoxy.

[0158] Furthermore, the compound is one of the following compounds:

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] The present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative, comprising the following steps:

[0201]

[0202] In a solvent, compound a, an organic base, TCDI or CDI and compound b react to give the compound shown in formula IV;

[0203] Rings R1, R2, R3, R4, R5, m, n, X1, X2, and A are as described above; X3 is S or O;

[0204] Preferably,

[0205] The solvent is dichloromethane;

[0206] And / or, the organic base is Et3N;

[0207] And / or, the reaction temperature is 25–40°C, and the reaction time is 10–12 hours.

[0208] The present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative, comprising the following steps:

[0209]

[0210] Step 1: In a solvent, compound c reacts with CH3I to give compound d;

[0211] Step 2: In a solvent, compound d reacts with ammonia to obtain the compound shown in formula IVa;

[0212] Rings R1, R2, R3, R4, R5, m, n, and A are as described above;

[0213] Preferably,

[0214] In step 1, the solvent is acetonitrile;

[0215] And / or, in step 1, the reaction temperature is 40–60°C and the reaction time is 4–10 hours;

[0216] And / or, in step 2, the solvent is acetonitrile;

[0217] And / or, in step 2, the reaction temperature is 80–100°C and the reaction time is 10–12 hours.

[0218] The present invention also provides the use of the aforementioned compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or crystal forms thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, in the preparation of medicaments having analgesic effects.

[0219] The present invention also provides a drug preparation which is a formulation made of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, plus pharmaceutically acceptable excipients.

[0220] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof.

[0221] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0222] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0223] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0224] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1 to C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms; "C1 to C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms.

[0225] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0226] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0227] "Cycloalkyl" refers to saturated or unsaturated all-carbon monocyclic or polycyclic (including fused, spiro, or bridged rings) that do not possess a conjugated π-electron system, such as, but not limited to: wait.

[0228] "Heterocyclic alkyl" refers to a cycloalkyl group in which at least one carbon atom on the ring is replaced by a heteroatom, which is O, N, and / or S, and is a saturated or unsaturated monocyclic or polycyclic (including fused, spiro, or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to: wait.

[0229] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused rings, spiro rings, or bridged rings) with a conjugated π-electron system, such as, but not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indeneyl. The aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. Furthermore, the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system, such as, but not limited to, [other types of rings]. wait.

[0230] "Heteroaryl" refers to an aryl group in which at least one carbon atom on the ring of a conjugated π-electron system is replaced by a heteroatom, which is O, N and / or S, such as including but not limited to thienyl, furanyl, isothiazolyl, etc.

[0231] "5-8 aryl" includes 5, 6, 7, and 8 aryl groups.

[0232] "5-8 aryl heteroaryl" includes 5, 6, 7, and 8 aryl heteroaryl.

[0233] "5- to 8-membered cycloalkyl groups" include 5, 6, 7, and 8-membered cycloalkyl groups.

[0234] "5- to 8-membered heterocyclic alkyl groups" include 5, 6, 7, and 8-membered heterocyclic alkyl groups.

[0235] The pharmaceutically acceptable salts described in this invention include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates, carbonates, bisulfates, sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hydrochlorides, hydrobromide, hydroiodates, hydroxyethyl sulfonates, lactates, malates, maleic acid esters, malonates, methyl sulfates, naphthates, theosulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxyacetate, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, sine sulfonates, methanesulfonates, p-toluenesulfonates, quaternary ammonium salts, or succinates, etc.

[0236] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0237] The compounds or pharmaceutical compositions of the present invention may be used in the following ways (but are not limited to): intragastric, enteric, parenteral (intravenous, intramuscular or subcutaneous), oral and various local administration methods.

[0238] Compositions intended for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0239] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0240] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0241] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0242] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0243] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0244] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0245] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0246] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dose administered is a pharmaceutically considered safe and effective dose.

[0247] Compared with the prior art, the compound provided by the present invention has the following beneficial effects:

[0248] This invention provides a compound with analgesic effects. This compound exhibits excellent analgesic efficacy, good safety profile, low toxicity and side effects, and does not induce dependence. Therefore, this compound has broad application prospects in the preparation of analgesic drugs, providing a new option for the clinical preparation of drugs with analgesic effects.

[0249] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0250] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0251] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0252] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3), deuterated methanol (d4-MeOH), and deuterated water (D2O). The internal standard was tetramethylsilane (TMS).

[0253] The LCMS assay was performed using an Agilent LCMS 1200-6120 (ESI) column: Waters Xbridge PrepC. 18 OBD 10μm 19*250mm. Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Gradient from 95% [water + 10mM ammonium bicarbonate] and 5% [CH3CN] to 5% [water + 10mM ammonium bicarbonate] and 95% [CH3CN] over 1.6 minutes, held at this condition for 1.4 minutes, then gradient to 95% [water + 10mM ammonium bicarbonate] and 5% [CH3CN] over 0.05 minutes, and held at this condition for 0.7 minutes.

[0254] (1) Medicinal materials and reagents

[0255] The thin-layer chromatography (TLC) silica gel plates used are manufactured by Qingdao Spectrum Separation Materials Co., Ltd., with specifications of 50*200mm and a thickness of 0.2~0.25mm.

[0256] Silica gel for column chromatography, 200-300 mesh, from Shandong Weihai Rushan Taiyang Desiccant Co., Ltd.

[0257] (2) Main instruments

[0258] Electronic balance, FA2004, Shanghai Liangping Instruments Co., Ltd.;

[0259] Temperature-controlled and pressure-regulating magnetic stirrer, TY98-1, Shanghai Sile Instruments Co., Ltd.

[0260] Three-in-one ultraviolet analyzer, ZF-2 model, Shanghai Anting Scientific Instrument Factory;

[0261] Rotary evaporator, R201, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0262] Liftable water bath, R201D, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0263] Circulating water vacuum pump (benchtop), SHB-III, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0264] Circulating water vacuum pump (portable), SHB-B95, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0265] Cryogenic circulating pump, DLSB-5 / 20, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0266] Rotary vane vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory.

[0267] Example 1: Preparation of compound 1-1-1 of the present invention

[0268]

[0269] 1. Synthesis of 110-2

[0270] Add 110-1 (5.0 g, 37 mmol) and a tetrahydrofuran solution of dimethylamine (2 N, 100 mL) to a 250 mL sealed tube, and stir at 70 °C for three days. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal-phase column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oily substance 110-2 (3.2 g, yield: 89.9%). MS Calcd.: 161.1 [M+H] + MS Found: 161.4 [M+H] + .

[0271] 2. Synthesis of 110-3

[0272] Add 110-2 (3.2 g, 20 mmol) and diethyl ether (50 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Then add lithium aluminum hydride (2.5 N·m THF, 16 mL) and stir overnight at room temperature. After the reaction is complete, slowly add water (3 mL), 15% sodium hydroxide (3 mL), and water (6 mL), stir at room temperature for 20 minutes, dry to anhydrous magnesium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal phase column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain yellow oil 110-3 (2.0 g, 61% yield).

[0273] 3. Synthesis of compound 1-1-1

[0274] 110-3 (656 mg, 4.0 mmol) was added to a reaction flask and dissolved in dichloromethane (30 mL). Triethylamine (2.0 g, 20.0 mmol) and CDI (972 mg, 6.0 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-1 (452 ​​mg, 4.0 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse phase chromatography to give a white solid 1-1-1 (689.35 mg, 57%). MS Calcd.: 304.1 [M+H] + MS Found: 304.4 [M+H] + .

[0275] 1H NMR (400MHz, DMSO-d6) δ: 7.47 (dd, J=4.8, 2.8Hz, 1H), 7.23 (dd, J=2.4, 0.8Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 7.03-7.00 (m, 1H), 6 .89 (s, 1H), 6.81 (d, J = 8.0Hz, 1H), 6.37 (t, J = 6.0Hz, 1H), 6.23 (t, J = 5.6Hz, 1H), 4.24-4.20 (m, 4H), 2.60 (s, 6H), 2.25 (s, 3H).

[0276] Example 2: Preparation of compound 1-1-2 of the present invention

[0277]

[0278] 1. Preparation of compound 110-3

[0279] Compound 110-3 was prepared according to the method described in Example 1.

[0280] 2. Preparation of compound 1-1-2

[0281] To 20 mL of dichloromethane solution containing 2-(aminomethyl)-N,N,5-trimethylaniline (110⁻³, 492 mg, 3 mmol), TCDI (1.07 g, 3.6 mmol) and triethylamine (1.25 g, 12 mmol) were added. After stirring at room temperature for 2 hours, thiophene-3-methylamine (339 mg, 3.0 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to give a yellow solid 1-(2-(dimethylamino)-4-methylbenzyl)-3-(thiophene-3-ylmethyl)thiourea (compound 1-1-2, 500 mg, 52% yield). MS Calcd.: 320.1 [M+H] + MS Found: 320.2 [M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d6) δ: 8.2-7.87 (m, 2H), 7.74-7.70 (m, 1H), 7.51-7.49 (m, 1H), 7.31 (s, 1 H), 7.08 (d, J=4.4Hz, 2H), 6.92 (s, 1H), 6.84 (s, 1H), 4.65 (s, 4H), 2.57 (s, 6H), 2.26 (s, 3H).

[0283] Example 3: Preparation of compound 1-1-3 of the present invention

[0284]

[0285] 1. Preparation of compound 1-1-2

[0286] Compound 1-1-2 was prepared according to the method described in Example 2.

[0287] 2. Synthesis of AL-37-23-188-A

[0288]

[0289] Iodomethane (800 mg, 6 mmol) was added to 20 mL of acetonitrile solution containing 1-1-2 (319 mg, 1 mmol), and the mixture was stirred at 40 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue. The crude residue was purified by column chromatography (DCM / MeOH = 30 / 1) to give a pale yellow oily mixture of (Z)-N-(2-(dimethylamino)-4-methylbenzyl)-N′-(thiophene-3-ylmethyl)aminothiocarbamate and (Z)-N'-(2-(dimethylamino)-4-methylbenzyl)-N-(thiophene-3-ylmethyl)aminothiocarbamate (AL-37-23-188-A 200 mg, 60% yield).

[0290] 3. Synthesis of compound 1-1-3

[0291]

[0292] Ammonia (600 mg, 6.0 mmol) was added to 10 mL of acetonitrile solution containing a mixture of (Z)-N-(2-(dimethylamino)-4-methylbenzyl)-N′-(thiophen-3-ylmethyl)aminothiocarbamate and (Z)-N'-(2-(dimethylamino)-4-methylbenzyl)-N-(thiophen-3-ylmethyl)aminothiocarbamate (AL37-23-188-A, 200 mg, 0.6 mmol). The mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to give a white solid 1-(2-(dimethylamino)-4-methylbenzyl)-3-(thiophen-3-ylmethyl)guanidine (compound 1-1-3, 30 mg, 17% yield). MS Calcd.: 303.2 [M+H] + MS Found: 303.2 [M+H] + .

[0293] 1H NMR (400MHz, DMSO-d6) δ: 7.50-7.48 (m, 3H), 7.29 (s, 1H), 7.13 (d, J=7.6Hz, 1H), 7.05-7.03 (m , 1H), 6.93 (m, 1H), 6.84 (d, J=7.6Hz, 1H), 4.28 (s, 2H), 4.24 (s, 2H), 2.62 (s, 6H), 2.26 (s, 3H).

[0294] Example 4: Preparation of compound 1-1-4 of the present invention

[0295]

[0296] 1. Preparation of compound 110-3

[0297] Compound 110-3 was prepared according to the method described in Example 1.

[0298] 2. Synthesis of 189-1

[0299]

[0300] Triethylamine (606 mg, 6 mmol) was added to 20 mL of isopropanol solution containing 2-(aminomethyl)-N,N,5-trimethylaniline (110-3, 492 mg, 3 mmol) and SM-2 (714 mg, 3 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by column chromatography (DCM / MeOH = 30 / 1) to give a pale yellow oily (Z)-N′-cyano-N-(2-(dimethylamino)-4-methylbenzyl)carbamate (189-1, 500 mg, 54% yield).

[0301] 3. Synthesis of compound 1-1-4

[0302]

[0303] Triethylamine (303 mg, 3 mmol) was added to 10 mL of isopropanol solution containing 189-1 (308 mg, 1 mmol) and thiophene-3-ylmethylamine (SM-1, 113 mg, 1 mmol), and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to obtain a white solid (Z)-N′-cyano-N-(2-(dimethylamino)-4-methylbenzyl)carbamate (compound 1-1-4, 104.74 mg, 32% yield).

[0304] 1H NMR (400MHz, DMSO-d6) δ: 7.83 (s, 1H), 7.61 (s, 1H), 7.52-7.50 (m, 1H), 7.25 (m, 1H), 7.05-7.02 (m, 2H), 6. 93 (s, 1H), 6.86 (t, J=7.6Hz, 1H), 4.33 (d, J=5.6Hz, 2H), 4.30 (d, J=6.0Hz, 2H), 2.52 (s, 6H), 2.26 (s, 3H).

[0305] Example 5: Preparation of compound 1-1-6 of the present invention

[0306]

[0307] 1. Preparation of compound 110-3

[0308] Compound 110-3 was prepared according to the method described in Example 1.

[0309] 2. Synthesis of compound 1-1-6

[0310] Under nitrogen protection at 0°C, bis(2,5-dioxopyrrolidone-1-yl) carbonate (922 mg, 3.6 mmol) was added to a 10 / 20 mL dichloromethane / acetonitrile mixture containing thiophene-3-ylmethanol (SM-3, 342 mg, 3 mmol). After stirring at room temperature for 4 hours, 110-3 (339 mg, 3 mmol) and triethylamine (909 mg, 9 mmol) were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by column chromatography and preparative liquid chromatography to obtain a grayish-white solid 1-1-6 (98.25 mg, 11% yield).

[0311] 1 H NMR (400MHz, DMSO-d6) δ: 7.62 (t, J=6.0Hz, 1H), 7.53 (dd, J=3.2Hz, 4.8Hz, 1H), 7.50 (s, 1H), 7.12-7.07 ( m, 2H), 6.89 (s, 1H), 6.81 (d, J=7.6Hz, 1H), 5.03 (s, 2H), 4.23 (d, J=6.0Hz, 2H), 2.59 (s, 6H), 2.25 (s, 3H).

[0312] Example 6: Preparation of compound 1-1-7 of the present invention

[0313]

[0314] CDI (389 mg, 2.4 mmol) and triethylamine (707 mg, 7.0 mmol) were added to 10 mL of DMF solution containing thiophene-3-ylmethylamine (SM-1, 226 mg, 2 mmol). After stirring at room temperature for 2 hours, 2-(dimethylamino)-4-methylphenyl)methanol (274-4, 330 mg, 2 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by column chromatography (DCM / MeOH = 50 / 1) to give a grayish-white solid 2-(dimethylamino)-4-methylbenzyl(thiophene-3-ylmethyl)carbamate (compound 1-1-7, 57.98 mg, 10% yield). MS Calcd.: 305.2 [M+H] + MS Found: 305.2 [M+H] +

[0315] 1 H NMR (400MHz, DMSO-d6) δ: 7.73 (t, J=6.0Hz, 4.8Hz, 1H), 7.47 (dd, J=3.2Hz, 4.8HZ, 1H), 7.25 (s, 1H), 7.20 (d, J=7.6Hz, 1H) , 7.02 (d, J = 4.8Hz, 1H), 6.93 (s, 1H), 6.84 (d, J = 7.6Hz, 1H), 5.06 (s, 2H), 4.19 (d, J = 6.0Hz, 2H), 2.62 (s, 6H), 2.25 (s, 3H).

[0316] Example 7: Preparation of compound 1-1-8 of the present invention

[0317]

[0318] 1. Preparation of compound 110-3

[0319] Compound 110-3 was prepared according to the method described in Example 1.

[0320] 2. Synthesis of Compound 191-1

[0321]

[0322] Triethylamine (606 mg, 6 mmol) was added to 20 mL of ethanol solution containing 2-(aminomethyl)-N,N,5-trimethylaniline (110-3, 492 mg, 3 mmol) and 1,1-bis(methylthio)-2-nitrosoethylene (495 mg, 3 mmol), and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by column chromatography (DCM / MeOH = 40 / 1) to give a pale yellow oily N,N,5-trimethyl-2-(((1-(methylthio)-2-nitrovinyl)amino)methyl)aniline (191-1, 500 mg, 60% yield).

[0323] 3. Synthesis of 1-1-8

[0324]

[0325] Triethylamine (303 mg, 3 mmol) was added to 10 mL of an ethanol solution containing 191-1 (281 mg, 1 mmol) and thiophene-3-ylmethylamine (113 mg, 1 mmol), and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to give a white solid 1-1-8 (87.86 mg, 25% yield).

[0326] 1 H NMR (400MHz, DMSO-d6) δ: 10.29 (d, J=9.6Hz, 1H), 8.14-7.99 (m, 1H), 7.56-7.27 (m, 2H), 7.10- 6.84 (m, 3H), 6.35 (d, J=8.0Hz, 1H), 4.55-4.27 (m, 4H), 2.61 (s, 3H), 2.57 (s, 3H), 2.08 (s, 3H).

[0327] Example 8: Preparation of compound 1-1-10 of the present invention

[0328]

[0329] 1. Synthesis of 193-1

[0330]

[0331] SM-1 (200 mg, 1.77 mmol) was added to a reaction flask, dissolved in dichloromethane (10 mL), and then 193-0 (251 mg, 1.77 mmol) was added. The mixture was stirred overnight at room temperature under nitrogen atmosphere. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was then purified by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oily substance 193-1 (300 mg, yield: 76%). MS Calcd.: 224.1 [M+H] + MS Found: 224.3 [M+H] + .

[0332] 2. Preparation of compound 110-3

[0333] Compound 110-3 was prepared according to the method described in Example 1.

[0334] 3. Synthesis of 1-1-10

[0335]

[0336] Add 193-1 (200 mg, 0.90 mmol) to a reaction flask, dissolve in dichloromethane (5 mL), then add 110-3 (147 mg, 0.90 mmol), and stir overnight at room temperature under nitrogen atmosphere. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal-phase column chromatography [dichloromethane:methanol (100:1-20:1)] to give a yellow oil 1-1-10 (110.74 mg, yield: 35%). MS Calcd.: 356.1 [M+H] + MS Found: 356.4 [M+H] + .

[0337] 1 H NMR (400MHz, DMSO-d6+D2O) δ: 7.54 (dd, J=2.8, 4.8Hz, 1H), 7.39 (s, 1H), 7.13 (d, J=7.2Hz, 1H), 7 .07 (d, J=4.4Hz, 1H), 6.99 (s, 1H), 6.89 (d, J=7.6Hz, 1H), 4.71 (s, 4H), 2.61 (s, 6H), 2.27 (s, 3H).

[0338] Example 9: Preparation of compound 1-1-1-A of the present invention

[0339]

[0340] 1. Preparation of compound 110-3

[0341] Compound 110-3 was prepared according to the method described in Example 1.

[0342] 2. Preparation of 1-1-1-A

[0343] CDI (243 mg, 1.5 mmol) and triethylamine (500 mg, 5.0 mmol) were added to 10 mL of dichloromethane solution containing 110-3 (164 mg, 1.0 mmol), and the mixture was stirred at room temperature for 2 hours. Then, furan-3-ylmethylamine (100 mg, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the combined organic phases were concentrated under reduced pressure under vacuum to obtain a crude product, which was purified by preparative liquid chromatography to give a white solid 1-1-1-A (139.88 mg, 49% yield).

[0344] 1 H NMR (400MHz, DMSO-d6) δ: 7.59 (s, 1H), 7.50 (s, 1H), 7.08 (d, J = 7.6Hz, 1H), 6.89 (s, 1H), 6.81 (d, J = 7.6Hz, 1H) , 6.40 (s, 1H), 6.22 (t, J = 6.8Hz, 1H), 4.22 (t, J = 6.0Hz, 2H), 4.04 (t, J = 5.6Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H).

[0345] Example 10: Preparation of compound 1-1-27 of the present invention

[0346]

[0347] 1. Preparation of compound 110-3

[0348] Compound 110-3 was prepared according to the method described in Example 1.

[0349] 2. Preparation of compound 1-1-27

[0350] 110-3 (328 mg, 2.0 mmol) and triethylamine (606 mg, 6.0 mmol) were dissolved in dichloromethane (20 mL). N,N′-carbonyldiimidazole (389 mg, 2.4 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, 2-thiophene methylamine (226 mg, 2.0 mmol) was added to the system. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 40 / 1) and reverse-phase preparative chromatography to obtain compound 1-1-27 (100 mg, yield 33%).

[0351] 1H NMR (400MHz, DMSO-d6) δ7.36 (dd, J=2.8, 4.8Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.94 (t, J=3.6Hz, 1H), 6.89 (s, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.52 (t, J=5.6Hz, 1H), 6.29 (t, J=6.0Hz, 1H), 4.38 (d, J=6.0Hz, 2H), 4.23 (t, J=6.0Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H).

[0352] Example 11: Preparation of compound 1-1-64 of the present invention

[0353]

[0354] 1. Synthesis of 60-2

[0355]

[0356] 5 mL of concentrated sulfuric acid was added to 50 mL of a methanol solution containing 2-(4-bromo-2-nitrophenyl)acetic acid (60-1, 2.59 g, 10 mmol), and the mixture was heated under reflux for 20 hours. After the reaction was complete, 100 mL of water was slowly added to quench the reaction mixture, followed by extraction three times with ethyl acetate. The mixed organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The crude product was purified by column chromatography (PE / EA = 5 / 1) to give a pale yellow solid methyl 2-(4-bromo-2-nitrophenyl)acetate (60-2, 2.3 g, 84%).

[0357] 2. Synthesis of 60-3

[0358]

[0359] Pd(dppf)Cl2·DCM (680 mg, 0.84 mmol) was added to a toluene / water mixture (80 / 8 mL) containing 60-2 (2.3 g, 8.4 mmol), MeKBF3 (4.1 g, 33.6 mmol), and cesium carbonate (8.2 g, 25.2 mmol). The mixture was stirred at 100 °C for 6 hours. After the reaction was complete, 50 mL of 1 N hydrochloric acid aqueous solution was slowly added to quench the reaction mixture, followed by extraction three times with ethyl acetate. The mixed organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The crude product was purified by column chromatography (PE / EA = 5 / 1) to give a pale yellow oily substance 60-3 (2.3 g, 84%).

[0360] 3. Synthesis of 60-4

[0361]

[0362] 10% Pd / C (280 mg) was added to 100 mL of ethanol solution containing 60-3 (1.4 g, 6.7 mmol), and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated to obtain a pale yellow oily substance 60-4 (1.1 g, 92%).

[0363] 4. Synthesis of 60-5

[0364]

[0365] Sodium cyanoborohydride (775 mg, 12.3 mmol) was added to a 30 mL methanol solution containing 60-4 (1.1 g, 6.15 mmol), 30% formaldehyde (aqueous solution) (2.77 g, 36.9 mmol), and 5 mL acetic acid. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, 50 mL of water was slowly added to quench the reaction mixture, followed by extraction three times with ethyl acetate. The mixed organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The crude product was purified by column chromatography (PE / EA = 1 / 1) to give a colorless oily 2-(2-(dimethylamino)-4-methylphenyl)acetic acid ester (60-5, 700 mg, 55%).

[0366] 1 H NMR (400MHz, DMSO-d6) δ: 7.07 (d, J=7.6Hz, 1H), 6.96 (s, 1H), 6.83 (dd, J=7.6, 0.8Hz, 1H), 3.63 (s, 2H), 3.58 (s, 3H), 2.53 (s, 6H), 2.26 (s, 3H).

[0367] 5. Synthesis of 60-11

[0368]

[0369] Lithium hydroxide (425 mg, 10.14 mmol) was added to a methanol / water mixture (12 / 3 mL) containing 60-5 (700 mg, 3.38 mmol), and the mixture was stirred at 100 °C for 6 hours. After the reaction was complete, 4N citric acid aqueous solution was slowly added to the reaction system for quenching, and then the mixture was concentrated to obtain the residue. The crude product was purified by reversed-phase chromatography (H2O / MeCN = 3 / 1) to obtain colorless oily 2-(2-(dimethylamino)-4-methylphenyl)acetic acid (60-11, 600 mg, 92%).

[0370] 6. Synthesis of 60-10

[0371]

[0372] To 30 mL of DMF solution containing 60-11 (600 mg, 3.11 mmol), ammonium chloride (830 mg, 15.55 mmol), and DIPEA (1.7 g, 12.44 mmol), EDCI (886 mg, 4.67 mmol) and HOBT (610 mg, 4.67 mmol) were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction system was diluted with ethyl acetate and water, and then extracted with ethyl acetate. The mixed organic layer was dried over anhydrous sodium sulfate, filtered under vacuum, and concentrated to obtain the residue. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to give a white solid 2-(2-(dimethylamino)-4-methylphenyl)acetamide (60-10, 450 mg, 75%).

[0373] 1 H NMR (400MHz, DMSO-d6) δ: 7.35 (s, 1H), 7.06 (d, J=7.6Hz, 1H), 6.91 (s, 1H), 6.87 (s, 1 H), 3.63 (s, 2H), 6.79 (dd, J=7.6, 0.8Hz, 1H), 3.42 (s, 2H), 2.58 (s, 6H), 2.25 (s, 3H).

[0374] 7. Synthesis of 60-9

[0375]

[0376] Under nitrogen protection at 0°C, BH3-THF (1.0N in THF, 4.0mL) was added to 10mL of tetrahydrofuran solution containing 60-10 (192mg, 1.0mmol), and the mixture was stirred at 70°C for 16 hours. After the reaction was complete, 2mL of 1N hydrochloric acid solution was slowly added to the reaction system to quench the reaction, and the solution was concentrated to obtain a grayish-white solid 2-(2-aminoethyl)-N,Nv5-trimethylaniline hydrochloride (60-9, 250mg, 100%).

[0377] 8. Synthesis of compound 1-1-64

[0378]

[0379] Triethylamine (30 mg, 3.0 mmol), CDI (124.5 mg, 0.75 mmol), and diethyl ether (204 mg, 2.0 mmol) were added to 20 mL of DCM solution containing 60-9 (108 mg, 0.5 mmol). The mixture was stirred at room temperature for 2 hours, and then thiophene-3-ylmethylamine (57.5 mg, 0.5 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the crude residue was concentrated under vacuum and purified by preparative liquid chromatography to give a white solid 1-(2-(dimethylamino)-4-methylphenethyl)-3-(thiophene-3-ylmethyl)urea (1-1-64, 43.60 mg, 27%).

[0380] 1 H NMR (400MHz, DMSO-d6) δ: 7.47-7.45 (m, 1H), 7.20 (d, J=2.0Hz, 1H), 7.05-6.99 (m, 2H), 6.92 (s, 1H), 6.30 (d, J=3.2Hz, 1H), 6.25 (s, 1H), 5.93 (t, J=5.6Hz, 1H), 4.17 (t, J=5.2Hz, 2H), 3.27-3.21 (m, 2H), 2.72-2.69 (m, 2H), 2.58 (s, 6H), 2.25 (s, 3H).

[0381] Example 12: Preparation of compound 1-1-66 of the present invention

[0382]

[0383] CDI (486 mg, 3.0 mmol) and triethylamine (1.0 g, 10.0 mmol) were added to 20 mL of dichloromethane solution containing 2-(thiophen-3-yl)ethane-1-amine (254 mg, 2.0 mmol), and the mixture was stirred at room temperature for 2 hours. Then, 2-(aminomethyl)-N,N,5-trimethylaniline (110-3, 328 mg, 2.0 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the residue was concentrated under vacuum to obtain a crude product residue, which was purified by preparative liquid chromatography to give a white solid 1-(2-(dimethylamino)-4-methylbenzyl)-3-(2-(thiophen-3-yl)ethyl)urea (1-1-66, 138.87 mg, 22% yield).

[0384] 1H NMR (400MHz, DMSO-d6) δ: 7.46 (dd, J=4.8, 2.8Hz, 1H), 7.18-7.17 (m, 1H), 7.06 (d, J=8.0Hz, 1H), 7.01-6.99 (m, 1H), 6.88 (s, 1H), 6.81 (d, J=7.6H z, 1H), 6.21 (t, J=5.6Hz, 1H), 5.97 (t, J=5.6Hz, 1H), 4.20 (t, J=5.6Hz, 2H), 3.29-3.24 (m, 2H), 2.70 (t, J=7.2Hz, 2H), 2.59 (s, 6H), 2.25 (s, 3H).

[0385] Example 13: Preparation of compound 1-1-63 of the present invention

[0386]

[0387] 1. Synthesis of 280-2

[0388]

[0389] Add 280-1 (2.2 g, 14.19 mmol) and a tetrahydrofuran solution of dimethylamine (2 N, 60 mL) to a 250 mL sealed tube, and heat under reflux for three days. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal column chromatography [petroleum ether:ethyl acetate (100:1-10:1)] to give a yellow oily substance 280-2 (3.2 g, yield: 89.9%). MS Calcd.: 181.1 [M+H] + MS Found: 181.4 [M+H] + .

[0390] 2. Synthesis of 280-3

[0391]

[0392] Add 280-2 (1.9 g, 10.56 mmol) to a reaction flask, dissolve in methanol (110 mL), then add Pd / C (380 mg). Purge the mixture three times with hydrogen, and stir overnight at room temperature under hydrogen atmosphere. After the reaction is complete, filter, remove the solvent under reduced pressure to obtain the crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to give a yellow oil 280-3 (1.26 g, 80% yield). MS Calcd.: 161.1 [M+H] + MS Found: 161.4 [M+H] + .

[0393] 3. Synthesis of 1-1-63

[0394]

[0395] Add 280-3 (220 mg, 1.08 mmol) to a reaction flask, dissolve in dichloromethane (6 mL), add triethylamine (436 mg, 4.32 mmol) and CDI (262 mg, 1.62 mmol), and stir at room temperature for two hours; then add SM-4 (122 mg, 1.08 mmol), and react overnight at room temperature. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed to obtain a white solid 1-1-63 (108.79 mg, 34%). MS Calcd.: 276.1 [M+H] + MS Found: 276.4 [M+H] + ...

[0396] 1 H NMR (400MHz, DMSO-d6) δ: 9.70 (s, 1H), 8.17 (s, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.43 (q, J = 13.6Hz, 1H) , 7.27 (q, J=2.0Hz, 1H), 6.70-6.98 (m, 2H), 6.82 (dd, J=1.2, 8.0Hz, 1H), 2.59 (s, 6H), 2.23 (s, 3H).

[0397] Example 14: Preparation of compound 1-1-107 of the present invention

[0398]

[0399] 1. Synthesis of 188-2-1

[0400]

[0401] Add 280-3 (550 mg, 3.67 mmol) to a reaction flask, dissolve in dichloromethane (10 mL), add triethylamine (1.48 g, 14.67 mmol) and TCDI (892 mg, 5.51 mmol), and stir at room temperature for two hours; then add SM-4 (363 mg, 3.67 mmol), and react overnight at room temperature. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed to obtain a white solid 188-2-1 (710 mg, 66.5%). MS Calcd.: 292.1 [M+H] + MS Found: 292.1 [M+H]+ .

[0402] 2. Synthesis of 188-2-2

[0403]

[0404] 188-2-1 (570 mg, 1.96 mmol) was added to a sealed tube and dissolved in MeCN (20 mL). Iodomethane (834 mg, 5.88 mmol) was then added, and the mixture was stirred at 40 °C for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] yielded a grayish-white solid, 188-2-2 (450 mg, 78%). MS Calcd.: 306.1 [M+H] + MS Found: 306.2 [M+H] + .

[0405] 3. Synthesis of 1-1-107

[0406]

[0407] 188-2-2 (430 mg, 1.41 mmol) was added to a sealed tube and dissolved in acetonitrile (15 mL), followed by ammonia (3 mL). The tube was sealed and the mixture was stirred at 80 °C for 5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] and preparative liquid chromatography yielded a grayish-white solid 1-1-107 (112.90 mg, 39.5%). MS Calcd.: 275.1 [M+H] + MS Found: 275.4 [M+H] + .

[0408] 1 H NMR (400MHz, CD3OD) δ: 7.38 (dd, J=3.2, 5.2Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 6.97 (dd, J=1.6, 2. 8Hz, 2H), 6.93 (dd, J=1.2, 4.8Hz, 1H), 6.86 (dd, J=1.2, 8.0Hz, 1H), 2.72 (s, 6H), 2.31 (s, 3H).

[0409] Example 15: Preparation of compound 1-1-188 of the present invention

[0410]

[0411] 1. Synthesis of 181-2

[0412]

[0413] Add 181-1 (3.0 g, 19.87 mmol) and a tetrahydrofuran solution of dimethylamine (2 N, 100 mL) to a 250 mL sealed tube, and stir at 70 °C for three days. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oily substance 181-2 (3.1 g, yield: 88.5%). MS Calcd.: 177.1 [M+H] + MS Found: 177.4 [M+H] + .

[0414] 2. Synthesis of 181-3

[0415]

[0416] Add 181-2 (2.0 g, 20 mmol) and Et2O (50 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Then add lithium aluminum hydride (2.5 N in THF, 16 mL) and stir overnight at room temperature. After the reaction is complete, slowly add water (2 mL), 15% sodium hydroxide (2 mL), and water (6 mL), stir at room temperature for 20 minutes, dry to anhydrous magnesium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain a yellow oil 181-3 (1.6 g, yield: 78%). MS Calcd.: 181.1 [M+H] + MS Found: 181.2 [M+H] + .

[0417] 3. Synthesis of 181-4

[0418]

[0419] 181-3 (420 mg, 2.32 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (937 mg, 9.28 mmol) and CDI (564 mg, 3.48 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. SM-1 (265 mg, 2.32 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. This crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1–20:1)] and the reaction proceeded in reverse to obtain a white solid 181-4 (420 mg, yield: 56.5%). MS Calcd.: 320.1 [M+H] + MS Found: 320.2 [M+H] + .

[0420] 1 H NMR (400MHz, DMSO-d6) δ: 7.47 (dd, J=2.8, 4.8Hz, 1H), 7.23 (dd, J=1.2, 3.2Hz, 1H), 7.11 (q, J=1.4Hz, 1H), 7.01 (dd, J=1.2, 4.8Hz, 1H), 6.6 0-6.58 (m, 2H), 6.36 (t, J=6.0Hz, 1H), 6.22 (t, J=6.0Hz, 1H), 4.19 (dd, J=6.0Hz, 1H), 6.23 (t, J=2.4, 5.6Hz, 4H), 3.72 (s, 3H), 2.60 (s, 6H).

[0421] 4. Synthesis of 1-1-188

[0422]

[0423] Add 181-4 (220 mg, 0.69 mmol) to the reaction flask, dissolve in tetrahydrofuran (10 mL), purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Add boron tribromide (2.07 mmol, 2.0 N in THF, 1.04 mL), and stir at room temperature for three hours. After the reaction is complete, slowly pour into water (10 mL), adjust pH to 9 with saturated sodium bicarbonate solution, extract three times with dichloromethane (20 mL), wash the organic phase once with saturated brine, separate the organic phase, dry to anhydrous magnesium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain a yellow oil 1-1-188 (51.37 mg, yield: 24.7%). MS Calcd.: 306.1 [M+H] + MS Found: 306.2 [M+H] + .

[0424] 1 H NMR (400MHz, DMSO-d6) δ: 9.19 (s, 1H), 7.47 (dd, J=4.8, 2.8Hz, 1H), 7.22 (dd, J=2.4, 0.8Hz, 1H), 7.02-6.98 (m, 2H), 6.47 (d, J=2.4Hz, 1H ), 6.40 (dd, J=2.4, 8.4Hz, 1H), 6.33 (t, J=5.6Hz, 1H), 6.15 (t, J=5.6Hz, 1H), 4.19 (d, J=6.0Hz, 2H), 4.15 (d, J=6.0Hz, 2H), 2.56 (s, 6H).

[0425] Example 16: Preparation of compound 1-1-177 of the present invention

[0426]

[0427] 1. Synthesis of 180-2

[0428]

[0429] Add 180-1 (1.0 g, 7.41 mmol) to a 100 mL reaction flask, dissolve in DMF (10 mL), add NaH (1.0 g, 7.41 mmol) at 0 °C, and react at room temperature for 2 h; then add CH3I (1.0 g, 7.41 mmol), and stir overnight at room temperature. After the reaction is complete, slowly pour the reaction solution into ice water, extract three times with dichloromethane (40 mL), dry the organic phase with anhydrous magnesium sulfate, filter, remove the solvent under reduced pressure to obtain the crude product, and purify by normal column chromatography [petroleum ether:ethyl acetate (100:1-10:1)] to obtain a brownish-yellow oil 180-2 (1.2 g, yield: 81%). MS Calcd.: 165.1 [M+H] + MS Found: 165.4 [M+H] + .

[0430] 2. Synthesis of 180-3

[0431]

[0432] Add 180-2 (602 mg, 3.01 mmol) and diethyl ether (20 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Then add lithium aluminum hydride (2.5 N in THF, 2.4 mL) and stir overnight at room temperature. After the reaction is complete, slowly add water (1 mL), 15% NaOH (3 mL), and water (3 mL), stir at room temperature for 20 minutes, dry to anhydrous magnesium sulfate, filter, remove solvent by vacuum distillation to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain yellow oil 180-3 (2.0 g, 61% yield).

[0433] 3. Synthesis of 1-1-177

[0434]

[0435] 180-3 (220 mg, 1.08 mmol) was added to a reaction flask and dissolved in dichloromethane (6 mL). Triethylamine (436 mg, 4.32 mmol) and CDI (262 mg, 1.62 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-1 (122 mg, 1.08 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 1-1-177 (125.06 mg, 34%). MS Calcd.: 344.2 [M+H] + MS Found: 344.4 [M+H] + .

[0436] 1 H NMR (400MHz, DMSO-d6) δ: 7.45 (dd, J=3.2, 5.2Hz, 1H), 7.21-7.16 (m, 2H), 7.16 (d, J=7.6Hz, 1H), 6.99 (dd, J=0.8, 4. 8Hz, 1H), 6.86-6.76 (m, 2H), 6.37 (t, J=5.6Hz, 1H), 6.31 (t, J=6.0Hz, 1H), 4.19 (dd, J=6.0, 9.2Hz, 4H), 2.60 (s, 6H).

[0437] Example 17: Preparation of compound 1-1-191 of the present invention

[0438]

[0439] 1. Synthesis of 217-1

[0440]

[0441] To 50 mL of tetrahydrofuran solution containing 2-amino-4-methylbenzonitrile (217-3, 660 mg, 5.0 mmol), 60% sodium hydride (440 mg, 11.0 mmol) was added. After stirring at room temperature for half an hour, deuterated iodomethane (1.45 g, 10.0 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, water was slowly added to quench the reaction mixture, followed by extraction with ethyl acetate. The mixed organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The crude product was purified by column chromatography (DCM / MeOH = 3 / 1) to give a yellow oily 2-(bis(methyl-d3)amino)-4-methylbenzonitrile (217-1, 680 mg, 82% yield).

[0442] 2. Synthesis of 217-2

[0443]

[0444] Under nitrogen protection at 0°C, lithium aluminum hydride (2.5N in THF, 1.6mL) was added to 20mL of diethyl ether solution containing 217-1 (332mg, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, 0.1mL of water, 0.1mL of 15% sodium hydroxide solution, and 0.3mL of water were slowly added sequentially to quench the mixture. The mixture was filtered and concentrated to obtain the residue. The crude product was subjected to silica gel rapid column chromatography (DCM:MeOH = 20:1) to obtain a yellow oily 2-(aminomethyl)-5-methyl-N,N-2-methyl(d3)aniline (217-2, 250mg, 74% yield).

[0445] 3. Synthesis of 1-1-191

[0446]

[0447] CDI (486 mg, 3.0 mmol) and triethylamine (1.0 g, 10.0 mmol) were added to 20 mL of dichloromethane solution containing 217-2 (340 mg, 2.0 mmol). After stirring at room temperature for 2 hours, thiophene-3-ylmethylamine (226 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to obtain a white solid 1-((1H-imidazol-2-yl)methyl)-3-(2-(dimethyl(d3)amino)-4-methylbenzyl)urea (1-1-191, 187 mg, 30% yield).

[0448] 1 H NMR (400MHz, DMSO-d6) δ; 7.46-7.45 (dd, J=2.8, 4.8Hz, 1H), 7.20 (dd, J=2.8, 1.2Hz, 1H), 7.05 (d, J=8.0Hz, 1H), 6.99 (dd, J=4.8, 1.2 Hz, 1H), 6.85 (s, 1H), 6.78 (d, J=8.0Hz, 1H), 6.35 (t, J=5.6Hz, 1H), 6.22 (t, J=6.0Hz, 1H), 4.19 (dd, J=6.0, 10.4Hz, 1H), 2.23 (s, 3H).

[0449] Example 18: Preparation of Compound 1-2-1 of the Present Invention

[0450]

[0451] 1. Synthesis of 140-2

[0452]

[0453] To a reaction flask, add 140-1 (3.0 g, 22.73 mmol), formaldehyde aqueous solution (8.5 g, 113.65 mmol), glacial acetic acid (5 mL), and methanol (45 mL). Under nitrogen protection, add sodium cyanoborohydride (7.2 g, 113.65 mmol), and then purge three times with a nitrogen balloon. Stir the mixture overnight at room temperature under nitrogen atmosphere. After the reaction is complete, pour the mixture into water (100 mL), extract three times with dichloromethane (100 mL), wash the organic phase with saturated brine (50 mL x 2), dry to anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain the crude product. Purify by reverse-phase column chromatography to give a yellow oily substance 140-2 (3.2 g, yield: 90%). MS Calcd.: 161.1 [M+H] + MS Found: 161.4 [M+H] + .

[0454] 2. Synthesis of 140-3

[0455]

[0456] Add 140-2 (600 mg, 3.75 mmol) and Et2O (20 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Then add lithium aluminum hydride (4.8 g, 22.0 mmol) and stir overnight at room temperature. After the reaction is complete, slowly add water (1 mL), 15% sodium hydroxide solution (1 mL), and water (3 mL), stir at room temperature for 20 minutes, dry to anhydrous magnesium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal column chromatography to obtain a yellow oily substance 140-3 (420 mg, 68%). MS Calcd.: 165.1 [M+H] + MS Found: 165.4 [M+H] + .

[0457] 3. Synthesis of Compound 1-2-1

[0458]

[0459] SM-1 (151 mg, 1.34 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (271 mg, 2.68 mmol) and CDI (326 mg, 2.01 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. 140-3 (220 mg, 1.34 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification was performed by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse chromatography to obtain a white solid compound 1-2-1 (83.75 mg, 21%). MS Calcd.: 304.1 [M+H] + MS Found: 304.2 [M+H] + .

[0460] 1 H NMR (400MHz, DMSO-d6) δ: 7.44 (dd, J=2.8, 4.8Hz, 1H), 7.19 (dd, J=1.2, 2.8Hz, 1H), 7.04-6.99 (m, 2H), 6.89 (d, J=1.2Hz, 1H) , 6.76 (dd, J=1.6, 7.6Hz, 1H), 6.29 (d, J=4.8Hz, 2H), 4.18 (d, J=5.6Hz, 2H), 4.13 (d, J=6.0Hz, 2H), 2.57 (s, 6H), 2.19 (s, 3H).

[0461] Example 19: Preparation of Compound 1-2-2 of the Present Invention

[0462]

[0463] 1. Synthesis of 140-3

[0464] Compound 140-3 was synthesized according to Example 18.

[0465] 2. Synthesis of compound 1-2-2

[0466] To a 20 mL solution of dichloromethane containing 5-(aminomethyl)-N,N,2-trimethylaniline (140-3, 492 mg, 3.0 mmol), TCDI (1.07 g, 3.6 mmol) and triethylamine (1.25 g, 12 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, thiophene-3-ylmethylamine (339 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to obtain a grayish-white solid 1-(3-(dimethylamino)-4-methylbenzyl)-3-(thiophene-3-ylmethyl)thiourea (compound 1-2-2, 500 mg, 52% yield).

[0467] Example 20: Preparation of compound 1-2-3 of the present invention

[0468]

[0469] 1. Synthesis of compound 1-2-2

[0470] Compound 1-2-2 was synthesized according to Example 19.

[0471] 2. Synthesis of compound 188-1-2

[0472]

[0473] Iodomethane (800 mg, 6 mmol) was added to 20 mL of acetonitrile solution containing compound 1-2-2 (319 mg, 1 mmol), and the mixture was stirred at 40 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated to obtain the residue. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to give a pale yellow oily methyl (Z)-N-(3-(dimethylamino)-4-methylbenzyl)-N′-(thiophene-3-ylmethyl)aminothiocarbamate (188-1-2, 200 mg, 60% yield).

[0474] 3. Synthesis of compound 1-2-3

[0475]

[0476] Ammonia (600 mg, 6.0 mmol) was added to 10 mL of acetonitrile solution containing 188-1-2 (200 mg, 0.6 mmol), and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid chromatography to give a white solid 1-(3-(dimethylamino)-4-methylbenzyl)-3-(thiophene-3-ylmethyl)guanidine (compound 1-2-3, 54.13 mg, 32% yield). MS Calcd.: 303.2 [M+H] + MS Found: 303.2 [M+H] + .

[0477] 1 H NMR (400MHz, DMSO-d6) δ: 7.50-7.48 (m, 3H), 7.27 (s, 1H), 7.07 (d, J=7.6Hz, 1H), 7.02 (d, J=4.8H z, 1H), 6.96 (s, 1H), 6.81 (d, J=7.6Hz, 1H), 4.31 (s, 2H), 4.25 (s, 2H), 2.60 (s, 6H), 2.19 (s, 3H).

[0478] Example 21: Preparation of compound 1-2-119 of the present invention

[0479]

[0480] 1. Synthesis of 188-6-2

[0481]

[0482] Add 188-6-1 (3.0 g, 19.35 mmol) and a tetrahydrofuran solution of dimethylamine (2 N, 100 mL) to a 250 mL sealed tube, and react overnight at 70 °C. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal column chromatography [petroleum ether: ethyl acetate (20:1-5:1)] to give a yellow oil 188-6-2 (3.0 g, yield: 86%). MS Calcd.: 181.1 [M+H] + MS Found: 181.3 [M+H] + .

[0483] 2. Synthesis of 188-6-3

[0484]

[0485] To a reaction flask, 188-6-2 (3.0 g, 16.67 mmol) was added and dissolved in 170 mL of methanol. Pd / C (600 mg) was then added, and the mixture was purged three times with a hydrogen balloon. The mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. This crude product was then purified by a normal column chromatography [dichloromethane:methanol (100:1–20:1)] to give a yellow oil, 188-6-3 (2.2 g, 88% yield). MS Calcd.: 151.1 [M+H] + MS Found: 151.4 [M+H] + .

[0486] 3. Synthesis of 188-6-4

[0487]

[0488] 188-6-3 (450 mg, 3.0 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (1.21 g, 12.0 mmol) and TCDI (729 mg, 4.5 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-1 (297 mg, 3.0 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 188-6-4 (610 mg, 69.9%). MS Calcd.: 292.1 [M+H] + MS Found: 292.1 [M+H] + .

[0489] 4. Synthesis of 188-6-5

[0490]

[0491] 188-6-4 (450 mg, 1.55 mmol) was added to a sealed tube and dissolved in acetonitrile (10 mL). Iodomethane (660 mg, 4.65 mmol) was then added, and the mixture was stirred at 40 °C for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] yielded a grayish-white solid, 188-6-5 (300 mg, 63.6%). MS Calcd.: 306.1 [M+H] + MS Found: 306.1 [M+H] + .

[0492] 5. Synthesis of 1-2-119

[0493]

[0494] 188-6-5 (350 mg, 1.15 mmol) was added to a sealed tube and dissolved in acetonitrile (12 mL), followed by the addition of ammonia (2 mL). The tube was sealed and the mixture was stirred at 80 °C for 5 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] yielded a grayish-white solid 1-2-119 (76.05 mg, 24%). MS Calcd.: 275.1 [M+H] + MS Found: 275.4 [M+H] + .

[0495] 1H NMR (400MHz, DMSO-d6) δ: 7.37 (dd, J=3.2, 5.2Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 7.02 (dd, J=1 .2, 2.4Hz, 1H), 6.97-6.94 (m, 2H), 6.80 (dd, J=2.4, 8.0Hz, 1H), 2.69 (s, 6H), 2.29 (s, 3H).

[0496] Example 22: Preparation of compound 1-1-9 of the present invention

[0497]

[0498] 1. Synthesis of compound 192-1

[0499]

[0500] Sodium hydride (2.42 g, 60.60 mmol) was slowly added to tetrahydrofuran (150 mL) at 0 °C. Under nitrogen protection, 192-1-4 (3.0 g, 30.30 mmol) was dissolved in tetrahydrofuran (30 mL) and slowly added dropwise to the reaction system. The mixture was stirred at room temperature for 30 minutes. Then, iodomethane (8.6 g, 60.60 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was slowly poured into ice water, filtered, and the filter cake was washed three times with water (5 mL) to obtain a brown solid 192-1-2 (3.0 g, yield: 48.8%).

[0501] 2. Synthesis of Compound 110-3

[0502] Compound 110-3 was synthesized according to Example 1.

[0503] 3. Synthesis of compound 192-2

[0504]

[0505] 192-1 (1.0 g, 4.93 mmol) and 110-3 (808 mg, 4.93 mmol) were added to a microwave-safe tube and dissolved in 20 mL of ethanol. The mixture was stirred in a microwave oven at 78 °C for 10 minutes. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] gave a grayish-white solid, 192-2 (1.0 g, yield: 63.7%). MS Calcd.: 320.1 [M+H] + MS Found: 320.2 [M+H] +

[0506] 4. Synthesis of compound 1-1-9

[0507]

[0508] 192-2 (230 mg, 0.72 mmol) and SM-1 (82 mg, 0.72 mmol) were dissolved in ethanol (1 mL) in a single-necked flask, followed by the addition of triethylamine (218 mg, 2.16 mmol). The mixture was stirred at 78 °C for two days under nitrogen atmosphere. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] yielded a grayish-white solid 1-1-9 (420 mg, 68%). MS Calcd.: 385.1 [M+H] + MS Found: 385.4 [M+H] + .

[0509] 1 H NMR (400MHz, DMSO-d6) δ: 8.30-8.22 (m, 2H), 7.56 (dd, J=2.8, 4.8Hz, 1H), 7.41 (q, J=1.2Hz, 1H), 7.20 (s, 1H), 7.07 (dd, J=1.6, 5.2 Hz, 1H), 6.97 (s, 1H), 6.88 (d, J=7.6Hz, 1H), 4.55 (d, J=5.2Hz, 2H), 4.67 (d, J=4.4Hz, 2H), 3.73 (s, 3H), 6.46 (s, 6H), 2.27 (s, 3H).

[0510] Example 23: Preparation of compound 1-1-1-B of the present invention

[0511]

[0512] 1. Synthesis of compound 110-3

[0513] Compound 110-3 was synthesized according to Example 1.

[0514] 1. Synthesis of compound 1-1-1-B

[0515] CDI (296.09 mg, 1.826 mmol) was added to a tetrahydrofuran (10 mL) solution containing compound 110-3 (300 mg, 1.826 mmol), and the mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, SM-16 (177.39 mg, 1.826 mmol) was added, and the mixture was stirred at 80 °C for 2.5 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by slurrying in acetonitrile to give an off-white solid 1-1-1-B (157.8 mg, yield 30.07%). MS Calcd.: 288.1 [M+H] +MS Found: 288.1 [M+H] + .

[0516] 1 HNMR (400MHz, DMSO-d6) δ7.56 (s, 1H), 7.08 (d, J=8.0Hz, 1H), 6.89 (s, 1H), 6.82 (d, J=8 .0Hz, 1H), 6.38(s, 2H), 6.25-6.19(m, 2H), 4.22(brs., 4H), 2.60(s, 6H), 2.25(s, 3H).

[0517] Example 24: Preparation of compound 1-1-14 of the present invention

[0518]

[0519] SM-1 (150 mg, 1.33 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (537 mg, 5.32 mmol) and CDI (324 mg, 2.00 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 13-1-1 (200 mg, 1.33 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 1-1-14 (160 mg, yield: 41.6%). MS Calcd.: 290.1 ​​[M+H] + MS Found: 290.4 [M+H] + .

[0520] 1 H NMR (400MHz, DMSO-d6) δ: 7.47 (q, J=2.8Hz, 1H), 7.24-7.17 (m, 3H), 7.08 (d, J=7.2Hz, 1H), 7.03-6.99 (m, 2H ), 6.39 (t, J=5.6Hz, 1H), 6.29 (t, J=6.0Hz, 1H), 4.28 (d, J=6.0Hz, 2H), 4.21 (d, J=6.0Hz, 2H), 2.61 (s, 6H).

[0521] Example 25: Preparation of compound 1-1-28 of the present invention

[0522]

[0523] 1. Synthesis of compound 110-3

[0524] Compound 110-3 was synthesized according to Example 1.

[0525] 2. Synthesis of compound 1-1-28

[0526] SM-5 (500 mg, 4.39 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.33 g, 13.16 mmol) and TCDI (781 mg, 4.39 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. 110-3 (720 mg, 4.39 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 0–3%) to give a pale yellow solid 1-1-28 (405 mg, yield: 29%). MS Calcd.: 320.1 [M+H] + MS Found: 320.4 [M+H] + .

[0527] 1 H NMR (400MHz, CD3OD) δ7.35 (dd, J=0.8, 4.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.06 (s, 1H), 7.02 ( d, J=3.2Hz, 1H), 6.97 (q, J=5.2Hz, 2H), 4.57 (s, 2H), 4.34 (s, 2H), 2.63 (s, 6H), 2.32 (s, 1H).

[0528] Example 26: Preparation of compound 1-1-29 of the present invention

[0529]

[0530] 1. Synthesis of compound 1-1-28

[0531] Compound 110-3 was synthesized according to Example 25.

[0532] 2. Synthesis of compound 1-1-29

[0533] 1-1-28 (280 mg, 0.88 mmol) was added to a reaction tube and dissolved in acetonitrile (10 mL). Then, 7N ammonia (5 mL) and lead carbonate (596 mg, 2.19 mmol) were added to the reaction system, and the mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–5%) and reverse-phase preparative chromatography to obtain a white solid 1-1-29 (143.92 mg, yield: 54%).

[0534] 1H NMR (400MHz, CD3OD) δ7.35 (dd, J=0.8, 4.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.06 (s, 1H), 7.02 ( d, J=3.2Hz, 1H), 6.97 (q, J=5.2Hz, 2H), 4.57 (s, 2H), 4.34 (s, 2H), 2.63 (s, 6H), 2.32 (s, 1H).

[0535] Example 27: Preparation of compound 1-1-40 of the present invention

[0536]

[0537] 13-1-1 (300 mg, 2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (606 mg, 6.0 mmol) and CDI (630 mg, 2.4 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-5 (226 mg, 2.0 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography to give a white solid 1-1-40 (156 mg, yield 26%). MS Calcd.: 290.1 ​​[M+H] + MS Found: 290.4 [M+H] + .

[0538] 1 H NMR (400MHz, DMSO-d6) δ7.36 (dd, J=4.8, 1.2Hz, 1H), 7.22-7.17 (m, 2H), 7.08 (d, J=7.2Hz, 1H), 7.02-6.98 (m, 1H), 6.95 -6.93 (m, 2H), 6.53 (d, J = 6.0Hz, 1H), 6.34 (d, J = 6.0Hz, 1H), 4.39 (d, J = 6.0Hz, 2H), 4.28 (d, J = 5.6Hz, 2H), 2.61 (s, 6H).

[0539] Example 28: Preparation of compound 1-1-41 of the present invention

[0540]

[0541] 1. Synthesis of compound SM-6

[0542]

[0543] SM-5 (2.05 mL, 20 mmol, 1.0 equiv.) was dissolved in EtOH (40 mL), followed by the addition of carbon disulfide (3.61 mL, 60 mmol, 3.0 equiv.) and triethylamine (2.78 mL, 20 mmol, 1.0 equiv.) at room temperature. The reaction was allowed to proceed for 1 hour at room temperature. Then, DMAP (73 mg, 0.6 mmol, 0.03 equiv.) and Boc₂O (4.6 mL, 20 mmol, 1.0 equiv.) were added at 0 °C, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 40:1) to give a yellow oily compound SM-6 (2.72 g, 88% yield).

[0544] 2. Synthesis of compound 1-1-41

[0545]

[0546] Weigh 13-1-1 (180 mg, 1.2 mmol, 1.1 equiv) into a 10 mL flask, add toluene (3 mL) and SM-6 (150 mg, 1.0 mmol, 1.0 equiv), and stir at room temperature for 2 h. The reaction solution is purified by silica gel column chromatography (DCM) to give a white solid 1-1-41 (205 mg, 0.67 mmol, 66% yield), m / z: [M+H]. + Calcd for C 15 H 19 N3S2H + 306.4655; Found 306.1108.

[0547] 1 H NMR (400MHz, CDCl3) δ7.29 (d, J=7.5Hz, 1H), 7.26 (d, J=1.9Hz, 1H), 7.23 (dd, J=4.5, 1.9Hz, 1H), 7.16-7.05 (m, 2H), 6.95 (d, J=4.6Hz, 2H), 4.94 (s, 2H), 4.40 (s, 2H), 2.49 (s, 6H).HRMS (ESI-TOF)

[0548] Example 29: Preparation of compound 1-1-174 of the present invention

[0549]

[0550] 1. Synthesis of compound 1-181-2

[0551]

[0552] To a 250 mL sealed tube, add 1-181-1 (2.0 g, 10.58 mmol) and dimethylaminetetrahydrofuran (2.0 N in THF, 70 mL), and stir at 70 °C for three days. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oil 1-181-2 (2.0 g, yield: 88.0%). MS Calcd.: 215.1 [M+H] + MS Found: 215.3 [M+H] + .

[0553] 2. Synthesis of compound 1-181-3

[0554]

[0555] Add 1-181-2 (1.0 g, 4.67 mmol) and THF (20 mL) to a reaction flask, purge three times with a nitrogen balloon, and cool to 0°C in an ice bath. Slowly add LAH (2.5 N in THF, 3.74 mL, 9.34 mmol), and stir overnight at room temperature. After the reaction is complete, cool the system to 0°C, slowly add water (1 mL), 15% sodium hydroxide solution (1 mL), and water (3 mL), stir at room temperature for 20 minutes, dry to anhydrous magnesium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to give yellow oil 1-181-3 (700 mg, yield: 70%). MS Calcd.: 219.1 [M+H] + MS Found: 219.3 [M+H] + .

[0556] 3. Synthesis of compound 1-1-174

[0557]

[0558] SM-5 (250 mg, 2.21 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (670 mg, 6.64 mmol) and CDI (358 mg, 2.21 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 1-181-3 (482 mg, 2.21 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 1-1-174 (166.54 mg, yield: 21%). MS Calcd.: 357.1 [M+H] + MS Found: 357.3 [M+H] + .

[0559] 1 H NMR (400MHz, DMSO-d6) δ: 7.42-7.34 (m, 3H), 7.30 (s, 1H), 6.95 (t, J=3.6Hz, 2H), 6.63 (t, J=6 .0Hz, 1H), 6.52 (t, J=6.0Hz, 1H), 4.39 (d, J=6.0Hz, 2H), 4.33 (d, J=5.6Hz, 1H), 2.68 (s, 6H).

[0560] Example 30: Preparation of compound 1-2-14 of the present invention

[0561]

[0562] 1. Synthesis of compound 13-2-1

[0563]

[0564] 13-2-0 (2.4 g, 20 mmol), formaldehyde aqueous solution (6.0 g, 80 mmol), and acetic acid (5 mL) were dissolved in 45 mL of methanol. NaBH3CN (2.5 g, 40 mmol) was then added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was complete, saturated brine (50 mL) was added to the reaction system, and the mixture was extracted with dichloroethane (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give a pale yellow oily compound 13-2-1 (1.5 g, yield 51%). MS Calcd.: 147.1 [M+H] + MS Found: 147.2 [M+H] + .

[0565] 2. Synthesis of compound 13-2-2

[0566]

[0567] 13-2-1 (1.46 g, 10 mmol) was dissolved in 150 mL of tetrahydrofuran. 2.5 N lithium aluminum hydride solution (8 mL, 20 mmol) was added dropwise to the reaction system at 0 °C. The reaction mixture was then stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with water (1.0 mL), 15% sodium hydroxide aqueous solution (1.0 mL), and water (3.0 mL). The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give a pale yellow oily compound 13-2-2 (900 mg, yield 60%). MS Calcd.: 151.1 [M+H] + MS Found: 151.2 [M+H] + .

[0568] 3. Synthesis of compound 1-2-14

[0569]

[0570] 13-2-2 (300 mg, 2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (606 mg, 6.0 mmol) and CDI (630 mg, 2.4 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-1 (226 mg, 2.0 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography to obtain a white solid 1-2-14 (159 mg, yield 28%). MS Calcd.: 290.1 ​​[M+H] + MS Found: 290.2 [M+H] + .

[0571] 1 H NMR (400MHz, DMSO-d6) δ7.46 (dd, J=4.8, 1.2Hz, 1H), 7.21 (t, J=3.6Hz, 1H), 7.10 (t, J=8.0Hz, 1H), 7.02 (dd, J=5 .2, 1.2Hz, 1H), 6.61-6.55 (m, 3H), 6.33-6.27 (m, 2H), 4.21 (d, J=6.0Hz, 2H), 4.16 (d, J=5.6Hz, 2H), 2.86 (s, 6H).

[0572] Example 31: Preparation of compound 1-2-27 of the present invention

[0573]

[0574] 1. Synthesis of 140-3

[0575] Compound 140-3 was synthesized according to Example 18.

[0576] 2. Synthesis of compound 1-2-27

[0577] SM-5 (250 mg, 2.21 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (670 mg, 6.64 mmol) and CDI (358 mg, 2.21 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. 140-3 (362 mg, 2.21 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification was performed by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse chromatography to obtain a white solid 1-2-27 (108.79 mg, 34%). MS Calcd.: 303.2 [M+H] + MS Found: 303.4 [M+H] + .

[0578] 1 H NMR (400MHz, DMSO-d6) δ: 7.36 (q, J=2.0Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 6.95-6.92 (m, 3H), 6.79 (d, J=7.2Hz, 1H), 6. 46 (t, J=5.6Hz, 1H), 6.38 (t, J=5.6Hz, 1H), 4.38 (d, J=6.0Hz, 2H), 4.15 (d, J=6.0Hz, 2H), 2.59 (s, 6H), 2.21 (s, 3H).

[0579] Example 32: Preparation of compound 1-2-28 of the present invention

[0580]

[0581] 1. Synthesis of 140-3

[0582] Compound 140-3 was synthesized according to Example 18.

[0583] 2. Synthesis of compound 1-2-28

[0584] SM-5 (600 mg, 5.31 mmol) was added to a reaction flask and dissolved in dichloromethane (30 mL). Triethylamine (1.60 g, 15.93 mmol) and TCDI (945 mg, 5.31 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 140-3 (870 mg, 5.31 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 1-2-28 (620 mg, 36%). MS Calcd.: 320.1 [M+H] + MS Found: 320.2 [M+H] + .

[0585] 1 H NMR (400MHz, DMSO-d6) δ: 7.96-7.73 (m, 2H), 7.40 (dd, J=1.2, 5.2Hz, 1H), 7.08 (d, J=6.0Hz, 1H), 7.01 (s, 1 H), 6.96 (q, J=3.6Hz, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 4.86 (s, 2H), 4.68 (s, 2H), 2.59 (s, 6H), 2.26 (s, 3H).

[0586] Example 33: Preparation of compound 1-2-29 of the present invention

[0587]

[0588] 1. Synthesis of 1-2-28

[0589] Compound 1-2-28 was synthesized according to Example 32.

[0590] 2. Synthesis of compound 1-2-28A

[0591]

[0592] 1-2-28 (320 mg, 1.0 mmol) was added to a sealed tube and dissolved in acetonitrile (20 mL). Iodomethane (426 mg, 3.0 mmol) was then added, and the tube was sealed and stirred overnight at 40 °C. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] yielded a grayish-white solid, 1-2-28A (300 mg, 90%). MS Calcd.: 334.2 [M+H] + MS Found: 334.4 [M+H] + .

[0593] 3. Synthesis of compound 1-2-29

[0594]

[0595] 1-2-28A (300 mg, 0.9 mmol) was added to a sealed tube and dissolved in acetonitrile (15 mL), followed by ammonia (5 mL). The tube was sealed and the mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] and preparative liquid chromatography yielded a grayish-white solid 1-2-29 (120.28 mg, 44%). MS Calcd.: 303.2 [M+H] + MS Found: 303.4 [M+H] + .

[0596] 1 H NMR (400MHz, CD3OD) δ: 7.34 (dd, J=1.2, 5.2Hz, 1H), 7.11 (d, J=7.6Hz, 1H), 7.02-6.96 (m, 3H) , 6.84 (dd, J=1.6, 8.0Hz, 1H), 4.59 (dd, J=0.8Hz, 2H), 4.34 (s, 2H), 2.66 (s, 6H), 2.28 (s, 3H).

[0597] Example 34: Preparation of compound 1-2-40 of the present invention

[0598]

[0599] 1. Synthesis of 13-2-2

[0600] Compound 13-2-2 was synthesized according to Example 30.

[0601] 2. Synthesis of 1-2-40

[0602] 13-2-2 (300 mg, 2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (606 mg, 6.0 mmol) and CDI (630 mg, 2.4 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-5 (226 mg, 2.0 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography to obtain a white solid 1-2-40 (163 mg, yield 28%). MS Calcd.: 290.2 [M+H] + MS Found: 290.2 [M+H] + .

[0603] 1 H NMR (400MHz, DMSO-d6) δ7.35 (dd, J=4.8, 1.2Hz, 1H), 7.09 (t, J=7.6Hz, 1H), 6.93 (d, J=3.6Hz, 2H), 6.61-6.53 ( m, 3H), 6.44 (d, J=6.0Hz, 1H), 6.34 (d, J=6.0Hz, 1H), 4.38 (d, J=6.0Hz, 2H), 4.15 (d, J=5.6Hz, 2H), 2.86 (s, 6H).

[0604] Example 35: Preparation of compound 1-2-1-A1 of the present invention

[0605]

[0606] 1. Synthesis of 140-3

[0607] Compound 140-3 was synthesized according to Example 18.

[0608] 2. Synthesis of 1-2-1-A1

[0609] CDI (295.89 mg, 1.826 mmol) was added to a tetrahydrofuran (10 mL) solution containing compound SM-32 (354.78 mg, 3.653 mmol), and the mixture was stirred at 25 °C for 1 hour. Then, compound 140-3 (300 mg, 1.826 mmol) was added, and the mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified by preparative liquid chromatography to give a white solid 1-2-1-A1 (264.2 mg, 50% yield). MS Calcd.: 288.2 [M+H] + MS Found: 288.1 [M+H] + .

[0610] 1 H NMR (400MHz, DMSO-d6) δ7.58-7.57 (m, 1H), 7.49-7.48 (m, 1H), 7.06-7.04 (m, 1H), 6.91 (s, 1H), 6.80-6.78 (m, J=1.3Hz, 1H), 6.40-6.39 (m, 1H), 6.29-6.26 (m, 1H), 6.18-6.15 (m, 1H), 4.15 (d, J=8Hz, 2H), 4.04 (d, J=4Hz, 2H), 2.60 (s, 6H), 2.21 (s, 3H).

[0611] Example 36: Preparation of compound 1-2-1-B1 of the present invention

[0612]

[0613] SM-16 (1.0 g, 10.3 mmol) was added to a flask and dissolved in tetrahydrofuran (50 mL). CDI (1.67 g, 10.3 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. 140-3 (1.69 g, 10.3 mmol) was added to the system, and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction mixture was poured into 100 mL of water and extracted with dichloromethane (50 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain a crude product. A small amount of ethyl acetate was added, and the mixture was stirred again. The filtrate was filtered, dissolved in a small amount of methanol, and then lyophilized with deionized water to obtain a white solid 1-2-1-B1 (667.39 mg, yield: 22.5%). MS Calcd.: 288.2 [M+H] + MS Found: 288.3 [M+H] + .

[0614] 1 H NMR (400MHz, DMSO-d6) δ7.54 (s, 1H), 7.05 (d, J=7.6Hz, 1H), 6.91 (s, 1H), 6.78 (d, J=7.6Hz, 1H), 6.37 (br, 1H), 6 .35-6.28 (m, 2H), 6.18 (d, J=2.8Hz, 1H), 4.21 (d, J=6.0Hz, 2H), 4.14 (d, J=6.0Hz, 2H), 2.60 (s, 6H), 2.21 (s, 3H).

[0615] Example 37: Preparation of compound 2-1-1 of the present invention

[0616]

[0617] 1. Synthesis of 1-3-4

[0618]

[0619] SM-6 (500 mg, 4.35 mmol) was dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (600 mg, 5.22 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was quenched in ice water, extracted three times with ethyl acetate, and the combined organic phases were washed with sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-3-4 (920 mg, yield: 100.00%). MS Calcd.: 194.0 [M+H]+ MS Found: 194.3 [M+H] + .

[0620] 2. Synthesis of 1-3-5

[0621]

[0622] Compound 1-3-4 (920 mg, 4.77 mmol) was dissolved in DMF (10 mL). Potassium phthalimide (1.06 g, 5.72 mmol) was added to the system, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was diluted with ethyl acetate, washed with ammonium chloride solution, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 / 1 to 2 / 1) to give compound 1-3-5 (930 mg, yield: 80%). MS Calcd.: 245.0 [M+H] + MS Found: 245.3 [M+H] +

[0623] 3. Synthesis of SM-7

[0624]

[0625] 1-3-5 (930 mg, 3.81 mmol) was dissolved in ethanol (40 mL), and hydrazine hydrate (65 mg, 0.29 mmol) was added at room temperature. The mixture was stirred at 80 °C for 30 minutes. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, diluted with dichloromethane, and poured into water. The mixture was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 2 / 1) to give compound SM-7 (2.2 g, yield: 83%).

[0626] 4. Synthesis of Compound 110-3

[0627] Compound 110-3 was synthesized according to Example 1.

[0628] 5. Synthesis of 2-1-1

[0629]

[0630] SM-7 (300 mg, 2.63 mmol) was dissolved in dichloromethane (10 mL) in a reaction flask. Triethylamine (1.06 g, 10.53 mmol) and CDI (639 mg, 3.95 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 110-3 (648 mg, 3.95 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 2-1-1 (177.87 mg, 22%). MS Calcd.: 305.1 [M+H] + MS Found: 305.1 [M+H] + .

[0631] 1 H NMR (400MHz, DMSO-d6) δ: 8.41 (d, J=1.6Hz, 1H), 7.21 (t, J=4.0Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.89 (s, 1H), 6.81 (d, J=7.6Hz , 1H), 6.73 (t, J=6.0Hz, 1H), 6.45 (t, J=6.0Hz, 1H), 4.51 (d, J=6.0Hz, 2H), 4.24 (d, J=6.0Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H).

[0632] Example 38: Preparation of compound 2-1-2 of the present invention

[0633]

[0634] 1. Synthesis of compound 110-3

[0635] Compound 110-3 was synthesized according to Example 1.

[0636] 2. Synthesis of 2-1-2

[0637] 110-3 (328 mg, 2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.01 g, 10.0 mmol) and CDI (324 mg, 2.0 mmol) were added to the reaction system, and the mixture was stirred at room temperature for two hours. Then, SM-8 (228 mg, 2.0 mmol) was added to the system, and the mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and reverse-phase preparative chromatography to obtain a white solid 2-1-2 (152.15 mg, yield: 25.6%). MS Calcd.: 305.1 [M+H]+ MS Found: 305.1 [M+H] + .

[0638] 1 H NMR (400MHz, DMSO-d6) δ8.94 (s, 1H), 7.72 (s, 1H), 7.07 (d, J = 7.6Hz, 1H), 6.89 (s, 1H), 6.80 (d, J = 8.0Hz, 1H), 6.5 8 (t, J=8.0Hz, 1H), 6.34 (t, J=5.6Hz, 1H), 4.43 (d, J=6.0Hz, 2H), 4.23 (d, J=5.6Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H).

[0639] Example 39: Preparation of compound 2-1-3 of the present invention

[0640]

[0641] 1. Synthesis of compound 110-3

[0642] Compound 110-3 was synthesized according to Example 1.

[0643] 2. Synthesis of 2-1-3

[0644] 110-3 (328 mg, 2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.01 g, 10.0 mmol) and CDI (324 mg, 2.0 mmol) were added to the reaction system, and the mixture was stirred at room temperature for two hours. Then, SM-9 (228 mg, 2.0 mmol) was added to the system, and the mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and reverse-phase preparative chromatography to obtain a white solid 2-1-3 (158.01 mg, yield: 26%). MS Calcd.: 305.1 [M+H] + MS Found: 305.4 [M+H] + .

[0645] 1H NMR (400MHz, DMSO-d6) δ7.70 (d, J=3.6Hz, 1H), 7.58 (d, J=3.2Hz, 1H), 7.11 (d, J=7.6Hz, 1H), 6.90 (s, 1H), 6.83-6.81 (m, 3H), 6.51 (t, J=5.6Hz, 2H), 4.50 (d, J=6.4Hz, 2H), 4.25 (d, J=6.0 Hz, 2H), 2.60 (s, 6H), 2.26 (s, 3H).

[0646] Example 40: Preparation of compound 3-1-1 of the present invention

[0647]

[0648] 1. Synthesis of compound 3-1-1-2

[0649]

[0650] Add 3-1-1-1 (2.6 g, 20.0 mmol) to the reaction flask, dissolve in tert-butanol (50 mL), then add triethylamine (2.02 g, 20.0 mmol) and DPPA (5.5 g, 20.0 mmol) to the reaction system. Stir the reaction mixture overnight at 80 °C. After the reaction is complete, cool to room temperature, add water (50 mL) to the reaction system, extract with ethyl acetate (3 × 50 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain crude product, and purify by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to obtain pale yellow solid 13-1-1-2 (1.8 g, yield: 45%). MS Calcd.: 201.1 [M+H] + MS Found: 202.2 [M+H] + .

[0651] 2. Synthesis of compound 3-1-1-3

[0652]

[0653] 3-1-1-2 (1.8 g, 9.0 mmol) was added to a reaction flask, and dioxane (50 mL) in 4N hydrochloric acid was added to dissolve it. The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation to give a white solid SM-10 (1.2 g, yield: 98%). MS Calcd.: 101.0 [M] + MS Found: 101.3 [M] + .

[0654] 3. Synthesis of 280-3

[0655] Compound 280-3 was synthesized according to Example 13.

[0656] 4. Synthesis of compound 3-1-1

[0657]

[0658] SM-10 (408 mg, 3.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.52 g, 15.0 mmol) and CDI (486 mg, 3.0 mmol) were added to the reaction system, and the mixture was stirred at room temperature for 4 hours. Then, 280-3 (408 mg, 3.0 mmol) was added to the system, and the mixture was stirred at 45 °C overnight. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and preparative liquid chromatography to obtain an off-white solid 3-1-1 (131.88 mg, yield: 17.5%).

[0659] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 8.73 (s, 1H), 8.18 (d, J=2.0Hz, 1H), 8.09 (dd, J=8.0, 1. 6Hz, 1H), 7.23 (dd, J=7.6, 1.6Hz, 1H), 7.09-6.99 (m, 2H), 6.80 (d, J=1.6Hz, 1H), 2.62 (s, 6H).

[0660] Example 41: Preparation of compound 3-1-2 of the present invention

[0661]

[0662] 1. Synthesis of SM-7

[0663] Compound SM-7 was synthesized according to Example 36.

[0664] 2. Synthesis of 3-1-2

[0665] SM-7 (220 mg, 1.93 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (585 mg, 5.79 mmol) and CDI (313 mg, 1.93 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. 13-1-1 (290 mg, 1.93 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification was performed by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and preparative liquid chromatography to give a white solid 3-1-2 (158.31 mg, yield: 28%). MS Calcd.: 291.1 [M+H]+ MS Found: 291.3 [M+H] + .

[0666] 1 H NMR (400MHz, CD3OD) δ8.38 (d, J=2.0Hz, 1H), 7.29 (d, J=7.2Hz, 1H), 7.26-7.16 (m, 3H), 7.07-7.03 (m, 1H), 4.67 (s, 2H), 4.45 (s, 2H), 2.69 (s, 6H).

[0667] Example 42: Preparation of compound 3-1-3 of the present invention

[0668]

[0669] 1. Synthesis of compound 110-3

[0670] Compound 110-3 was synthesized according to Example 1.

[0671] 2. Synthesis of 3-1-3

[0672] Add 110-3 (250 mg, 1.52 mmol) to a reaction flask, dissolve in dichloromethane (10 mL), then add triethylamine (462 mg, 4.57 mmol) and CDI (246 mg, 1.52 mmol) to the reaction system and stir at room temperature for two hours; then add SM-11 (149 mg, 1.52 mmol) and stir overnight at room temperature. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) to obtain a white solid 3-1-3 (56.35 mg, yield: 13%). MS Calcd.: 289.2 [M+H] + MS Found: 289.2 [M+H] + .

[0673] 1 H NMR (400MHz, DMSO-d6) δ8.45 (d, J=1.2Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 6.90 (s, 1H), 6.81 (d, J=7.6Hz, 1H), 6.61 (t, J=5 .2Hz, 1H), 6.42 (t, J=5.6Hz, 1H), 6.24 (s, 1H), 4.38 (d, J=6.0Hz, 2H), 4.23 (d, J=6.0Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H).

[0674] Example 43: Preparation of compound 3-1-4 of the present invention

[0675]

[0676] 1. Synthesis of compound 110-3

[0677] Compound 110-3 was synthesized according to Example 1.

[0678] 2. Synthesis of 3-1-4

[0679] CDI (486 mg, 3.0 mmol) and triethylamine (1.0 g, 10.0 mmol) were added to a solution of 110-3 (328 mg, 2.0 mmol) in dichloromethane (20 mL). The resulting mixture was stirred at room temperature for two hours, followed by the addition of SM-12 (340 mg, 2.0 mmol), and stirring was continued overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-4 (116.92 mg, 20% yield).

[0680] 1 H NMR (400MHz, DMSO-d6) δ: 11.77 (d, J=6.4Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.89 (t, J=4.0Hz, 3 H), 6.81 (d, J=7.6Hz, 1H), 6.39-6.37 (m, 2H), 4.25-4.21 (m, 4H), 2.60 (s, 6H), 2.25 (s, 3H).

[0681] Example 44: Preparation of compound 3-1-5 of the present invention

[0682]

[0683] 1. Synthesis of Compound 103-1

[0684]

[0685] 104-2A (485 mg, 2.37 mmol) was dissolved in 40 mL of dimethylamine, and the mixture was stirred at 70 °C for 3 days. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was then subjected to silica gel column chromatography to give 103-1 (387 mg, 80% yield). MS Calcd.: 231.1 [M+H] + MS Found: 231.3 [M+H] +

[0686] 2. Synthesis of Compound 103-2

[0687]

[0688] Pd / C (50 mg) was added to a methanol (20 mL) solution of 10³⁻¹ (387 mg, 1.68 mmol), and the mixture was stirred overnight at room temperature under hydrogen atmosphere at 0.5 MPa. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was then subjected to silica gel column chromatography (methanol / dichloromethane = 0.5%) to give a yellow solid 10³⁻² (232 mg, 80% yield). MS Calcd.: 233.1 [M+H] + MSFound: 233.4 [M+H] +

[0689] 3. Synthesis of compound 103-3

[0690]

[0691] Riney Ni (50 mg) was added to a methanol (20 mL) solution of 10³⁻² (232 mg, 1.0 mmol), and the mixture was stirred overnight at room temperature under hydrogen atmosphere at 0.5 MPa. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was then subjected to silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give a yellow solid 10³⁻³ (118 mg, 50% yield). MS Calcd.: 237.2 [M+H] + MS Found: 237.4 [M+H] +

[0692] 4. Synthesis of compound 3-1-5

[0693]

[0694] CDI (178 mg, 1.1 mmol) and triethylamine (363 mg, 3.6 mmol) were added to a solution of 10 mL of dichloromethane (103-3, 170 mg, 0.72 mmol). The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of SM-1 (81 mg, 0.72 mmol). The mixture was stirred overnight at room temperature until complete. The solvent was removed under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-5 (50.33 mg, 48.5% yield). MS Calcd.: 376.2 [M+H] + MSFound: 376.3 [M+H] +

[0695] 1H NMR (400MHz, DMSO-d6) δ: 7.47 (dd, J=4.8, 3.2Hz, 1H), 7.23 (d, J=2.0Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 7.01 (dd, J=4.8, 1.2Hz, 1H), 6.92 (d, J=1.6 Hz, 1H), 6.86-6.84 (m, 1H), 6.37 (t, J=6.0Hz, 1H), 6.25 (t, J=6.0Hz, 1H) , 4.24-4.20(m, 4H), 3.58(s, 3H), 2.82-2.76(m, 2H), 2.61-2.58(m, 8H).

[0696] Example 45: Preparation of compound 3-1-6 of the present invention

[0697]

[0698] 1. Synthesis of compound 104-8

[0699]

[0700] Lithium hydroxide (615 mg, 14.63 mmol) was added to a methanol / water (24 / 6 mL) solution of 104-2A (1.0 g, 4.88 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with water, acidified with citric acid to approximately pH 6, and filtered to obtain the crude product. Silica gel column chromatography yielded a white solid 104-8 (750 mg, 80% yield).

[0701] 1 H NMR (400MHz, DMSO-d6) δ: 12.76 (s, 1H), 7.96 (q, J=7.2Hz, 2H), 7.75 (d, J=8.4Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 6.79 (d, J=16Hz, 1H)

[0702] 2. Synthesis of compound 104-9

[0703]

[0704] 104-8 (900 mg, 4.71 mmol), methylamine hydrochloride (1.0 g, 4.88 mmol), EDCI (1.36 g, 7.07 mmol), and DIPEA (1.82 g, 14.13 mmol) were dissolved in 20 mL of DMF. The resulting mixture was stirred at room temperature for 30 minutes, followed by the addition of HOBT (954 mg, 7.07 mmol), and stirring continued overnight. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to give a white solid 104-9 (480 mg, 50% yield).

[0705] 3. Synthesis of compound 104-10

[0706]

[0707] 104-9 (480 mg, 1.68 mmol) was dissolved in dimethylamine (20 mL) and stirred at 70 °C for 48 hours. After the reaction was complete, the solution was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-2.5%) to give a yellow solid 104-10 (370 mg, 69% yield). MS Calcd.: 230.1 [M+H] + MS Found: 230.3 [M+H] + .

[0708] 4. Synthesis of compound 104-7

[0709]

[0710] Pd / C (68 mg) was added to a 20 mL solution of 10⁴⁻¹⁰ (340 mg, 1.47 mmol) in ethanol. The mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was then subjected to silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give a yellow solid 10⁴⁻⁷ (300 mg, 88% yield). MS Calcd.: 232.1 [M+H] + MSFound: 232.3 [M+H] + .

[0711] 5. Synthesis of compound 104-11

[0712]

[0713] At 0°C, lithium aluminum hydride (2.6 mmol) was added to a 5 mL solution of 104-7 (300 mg, 1.30 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, water (0.3 mL), 15% sodium hydroxide solution (0.3 mL), and water (0.6 mL) were added sequentially, and the resulting mixture was stirred for another 20 minutes at room temperature. The mixture was filtered to obtain a crude product, which was then subjected to silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give a yellow solid 104-11 (120 mg, 40% yield). MS Calcd.: 236.1 [M+H] + MS Found: 236.4 [M+H] + .

[0714] 6. Synthesis of compound 3-1-6

[0715]

[0716] CDI (178 mg, 1.1 mmol) and triethylamine (363 mg, 3.6 mmol) were added to a solution of 104-11 (169 mg, 0.72 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of SM-1 (81 mg, 0.72 mmol). The mixture was then stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-6 (88 mg, 33% yield). MS Calcd.: 375.2 [M+H] + MS Found: 375.4 [M+H] +

[0717] 1 H NMR (400MHz, DMSO-d6) δ: 7.75 (d, J=4.4Hz, 1H), 7.48-7.46 (m, 1H), 7.24-7.22 (m, 1H), 7.09 (d, J=8.0Hz, 1H), 6.90 (d, J=1.6Hz, 1H), 6.84-6.82 (m, 2H ), 6.37(t, J=6.8Hz, 1H), 6.25(t, J=5.6Hz, 1H), 4.24-4.20(m, 2H), 2.75(t , J=7.2Hz, 2H), 2.59 (s, 6H), 2.55 (t, J=4.8Hz, 3H), 2.32 (t, J=8.0Hz, 2H).

[0718] Example 46: Preparation of compound 3-1-7 of the present invention

[0719]

[0720] 1. Synthesis of compound 110-3

[0721] Compound 110-3 was synthesized according to Example 1.

[0722] 2. Synthesis of compound 3-1-7

[0723] CDI (243 mg, 1.5 mmol) and triethylamine (500 mg, 5.0 mmol) were added to a 10 mL solution of DMF containing 110-3 (164 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of SM-13 (99 mg, 1.0 mmol). The mixture was then stirred overnight at 80 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-7 (117 mg, 40% yield). MS Calcd.: 290.2 [M+H] + MS Found: 290.1 ​​[M+H] + .

[0724] 1 H NMR (400MHz, DMSO-d6) δ: 7.10 (d, J=8.0Hz, 1H), 6.88 (s, 1H), 6.81 (d, J=8.0Hz, 1H), 6.45 (s, 1H), 6.32 (s, 1H), 4.34-4.31 (s, 2H), 4.23 (t, J=6.0Hz, 2H), 2.59 (s, 6H), 2.25 (s, 3H).

[0725] Example 47: Preparation of compound 3-1-8 of the present invention

[0726]

[0727] 1. Synthesis of compound 18-2

[0728]

[0729] Potassium hydroxide (4.48 g, 80 mmol) was added to a methanol (500 mL) solution of 4-chloro-3,5-dinitrobenzoic acid (18-1, 9.8 g, 40 mmol), and the resulting mixture was stirred at 70 °C for 20 hours. After the reaction was complete, 500 mL of 3N hydrochloric acid solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography gave a pale yellow solid 18-2 (8.2 g, 85% yield).

[0730] 2. Synthesis of compound 18-11

[0731]

[0732] Concentrated sulfuric acid (10 mL) was added to a methanol (250 mL) solution of 4-methoxy-3,5-dinitrobenzoic acid (18-2, 8.2 g, 34 mmol), and the resulting mixture was stirred at 70 °C for 20 hours. After the reaction was complete, 200 mL of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography gave a pale yellow oil 18-11 (4.8 g, 55% yield).

[0733] 3. Synthesis of compound 18-12

[0734]

[0735] Pd / C (960 mg) was added to an ethanol (200 mL) solution of methyl 4-methoxy-3,5-dinitrobenzoate (18-11, 4.8 g, 18.8 mmol), and the resulting mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. After the reaction was complete, the solution was concentrated under reduced pressure to give a pale yellow oil, 18-12 (8.2 g, 85% yield).

[0736] 4. Synthesis of compounds 18-13

[0737]

[0738] NaBH3CN (5.7 g, 91.8 mmol) was added to a methanol (30 mL) solution of methyl 4-methoxy-3,5-diaminobenzoate (18-12, 3.0 g, 15.3 mmol), an aqueous solution of formaldehyde (11.5 g, 153 mmol), and acetic acid (10 mL). The mixture was stirred at room temperature for 20 hours. After the reaction was complete, the solution was alkalized to approximately pH 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography to give a light brown oily substance 18-13 (2.5 g, 65% yield).

[0739] 5. Synthesis of compounds 18-14

[0740]

[0741] Under nitrogen protection and an ice-water bath, lithium aluminum hydride (2.5N tetrahydrofuran solution, 8.0 mL) was added to a solution of methyl 4-methoxy-3,5-di(dimethylamino)benzoate (18-13, 2.5 g, 9.9 mmol) in diethyl ether (100 mL). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (0.8 mL), 15% sodium hydroxide solution (0.8 mL), and water (2.4 mL) were added sequentially. The mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to give a yellow oily substance 18-14 (1.7 g, 77% yield).

[0742] 6. Synthesis of compounds 18-15

[0743]

[0744] DEAD (5.29 g, 30.4 mmol) and PPh3 (3.0 g, 11.4 mmol) were added to a solution of 18-14 (1.7 g, 7.6 mmol) and 18-14-1 (1.12 g, 7.6 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to give a yellow oily substance 18-15 (1.5 g, 56% yield).

[0745] 7. Synthesis of Compound 18-6

[0746]

[0747] Hydrazine hydrate (353 mg, 8.4 mmol) was added to a 1.5 g (4.2 mmol) solution of ethanol (30 mL), and the resulting mixture was stirred at room temperature for 20 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH = 20 / 1) to give a light brown oily substance 18-6 (700 mg, 75% yield).

[0748] 8. Synthesis of compound 3-1-8

[0749]

[0750] CDI (220 mg, 1.35 mmol) and triethylamine (455 mg, 4.5 mmol) were added to a solution of 18-6 (200 mg, 0.9 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours, followed by the addition of SM-5 (102 mg, 0.9 mmol). The resulting mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography to give a light brown oily substance 3-1-8 (102 mg, 31% yield). MS Calcd.: 363.2 [M+H] +MS Found: 363.2 [M+H] + .

[0751] 1 H NMR (400MHz, DMSO-d6) δ: 7.43 (dd, J=4.8, 2.8Hz, 1H), 7.18 (dd, J=3.2, 1.2Hz, 1H), 6.98 (dd, J=4.8, 1.2Hz, 1 H), 6.40 (s, 2H), 6.30-6.26 (m, 2H), 4.18 (d, J=6.0Hz, 2H), 6.06 (d, J=6.0Hz, 2H), 3.58 (s, 3H), 2.68 (s, 12H).

[0752] Example 48: Preparation of compound 3-1-9 of the present invention

[0753]

[0754] 1. Synthesis of compound 21-2

[0755]

[0756] A mixture of 21-1 (1.66 g, 10 mmol) and phenol (1.04 g, 11 mmol) in tetrahydrofuran (50 mL) was added and stirred at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography to give 21-2 (2.0 g, 83% yield), a pale yellow solid.

[0757] 2. Synthesis of compound 21-3

[0758]

[0759] Pd / C (96 mg) was added to a 20 mL solution of ethanol containing 21-2 (480 mg, 2.0 mmol), and the resulting mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a pale yellow oil, 21-3 (400 mg, 95% yield).

[0760] 3. Synthesis of compound 21-4

[0761]

[0762] To a mixture of 21-3 (400 mg, 1.9 mmol), formaldehyde aqueous solution (2.85 g, 38 mmol), and acetic acid (3 mL) in methanol (10 mL), NaBH3CN (1.2 g, 19 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to alkalize to approximately pH 8. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography to give a light brown oily substance 21-4 (300 mg, 66% yield).

[0763] 4. Synthesis of Compound 21-5

[0764]

[0765] Under nitrogen protection and an ice-water bath, lithium aluminum hydride (2.5N tetrahydrofuran solution, 1.0 mL) was added to a 20 mL solution of 21-4 (2.5 g, 9.9 mmol) in diethyl ether. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, 0.2 mL of H₂O, 0.2 mL of 15% NaOH solution, and 0.6 mL of H₂O were added sequentially. The mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to give a yellow oily substance 21-5 (200 mg, 66% yield).

[0766] 5. Synthesis of compound 3-1-9

[0767]

[0768] CDI (207 mg, 1.25 mmol) and triethylamine (420 mg, 4.15 mmol) were added to a solution of 21-5 (200 mg, 0.83 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. Then, SM-5 (94 mg, 0.83 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-9 (190 mg, 60% yield). MS Calcd.: 382.2 [M+H] + MS Found: 382.4 [M+H] + .

[0769] 1H NMR (400MHz, DMSO-d6) δ: 7.42-7.40 (m, 1H), 7.37-7.35 (m, 1H), 7.17-7.07 (m, 3H), 7.97-6.92 (m, 4H), 6.87-6.84 (m, 1H), 6.41 (t, J=6.8Hz, 1H), 6.35 (t, J=5.6Hz, 1H), 4.28 (d, J=6.4Hz, 2H), 4.17 (d, J=5.6Hz, 2H), 2.61 (s, 6H).

[0770] Example 49: Preparation of compound 3-1-10 of the present invention

[0771]

[0772] 1. Synthesis of compound 19-2

[0773]

[0774] Add 19-1 (600 mg, 4.55 mmol) to a reaction flask, dissolve in methanol (25 mL), then add formaldehyde aqueous solution (3.69 g, 45.5 mmol), acetic acid (1.37 g, 22.75 mmol), and sodium cyanoborohydride (1.43 g, 22.75 mmol) sequentially. After addition, stir overnight at room temperature under nitrogen atmosphere. After the reaction is complete, quench the reaction with water (40 mL), extract three times with dichloromethane (40 mL), dry to anhydrous sodium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to obtain yellow oil 19-2 (560 mg, yield: 77%). MS Calcd.: 161.1 [M+H] + MS Found: 161.4 [M+H] + .

[0775] 2. Synthesis of Compound 19-3

[0776]

[0777] Add 19-2 (560 mg, 3.50 mmol) and tetrahydrofuran (15 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Then add lithium aluminum hydride (2.5 N in THF, 7.0 mmol, 2.8 mL) dropwise, and stir overnight at room temperature. After the reaction is complete, cool the system to 0 °C, slowly add water (0.6 mL), 15% sodium hydroxide aqueous solution (0.6 mL), and water (1.8 mL), stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter, remove solvent under reduced pressure to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain a yellow oily substance 19-3 (300 mg, yield: 52%). MS Calcd.: 164.2 [M+H] + MS Found: 164.4 [M+H] + .

[0778] 3. Synthesis of SM-7

[0779] Compound SM-7 was synthesized according to Example 36.

[0780] 4. Synthesis of compound 3-1-10

[0781]

[0782] SM-7 (209 mg, 1.83 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (554 mg, 5.49 mmol) and CDI (297 mg, 1.83 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. 19-3 (300 mg, 1.83 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared in reverse to give a white solid 3-1-10 (170.65 mg, yield: 31%).

[0783] 1 H NMR (400MHz, DMSO-d6) δ: 8.42 (d, J=1.6Hz, 1H), 7.22 (t, J=0.8Hz, 1H), 7.02 (s, 1H), 6.99 (d, J=1.2Hz, 2H), 6.76 (t, J=5.6Hz, 1H), 6.49 (t, J=5.6Hz, 1H), 4.53 (d, J=6.0Hz, 2H), 4.26 (d, J=6.0Hz, 2H), 2.58 (s, 6H), 2.22 (s, 3H).

[0784] Example 50: Preparation of compound 3-1-11 of the present invention

[0785]

[0786] 1. Synthesis of Compound 48-1

[0787]

[0788] Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added to a methanol (20 mL) solution of 48-1 (290 mg, 1.0 mmol) and triethylamine (404 mg, 4.0 mmol). The resulting mixture was stirred overnight at 80 °C under a CO atmosphere. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography to give a white solid 48-2 (200 mg, 74% yield).

[0789] 2. Synthesis of Compound 48-3

[0790]

[0791] 48-2 (200 mg, 0.74 mmol) was added to 10 mL of 4N dioxane hydrochloride solution and stirred at room temperature for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid 48-3 (150 mg, 93% yield).

[0792] 3. Synthesis of compound 110-3

[0793] Compound 110-3 was synthesized according to Example 1.

[0794] 4. Synthesis of compound 3-1-11

[0795]

[0796] CDI (178 mg, 1.1 mmol) and triethylamine (363 mg, 3.6 mmol) were added to a solution of 110-3 (118 mg, 0.72 mmol) in 10 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours, followed by the addition of 48-3 (150 mg, 0.72 mmol). The resulting mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-11 (98 mg, 52% yield). MS Calcd.: 362.2 [M+H] + MS Found: 362.4 [M+H] + .

[0797] 1H NMR (400MHz, DMSO-d6) δ: 7.64 (d, J=3.6Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 7.01 (d, J=3.6Hz, 1H), 6.89 (s, 1H), 6.81 (d, J=7.6Hz, 1H), 6.67 (s, 1H), 6.41 (t, J=5.6Hz, 1H), 4.41 (d, J=6.0Hz, 2H), 4.24 (d, J=5.6Hz, 2H), 3.80 (s, 3H), 2.60 (s, 6H), 2.26 (s, 3H).

[0798] Example 51: Preparation of compound 3-1-12 of the present invention

[0799]

[0800] 1. Synthesis of compound T1-2

[0801]

[0802] T1-1 (2.0 g, 14.26 mmol) was added to the reaction flask and dissolved in DMF (40 mL). Then, NBS (2.54 g, 14.26 mmol) was added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5%) to give a colorless oily compound T1-2 (3.00 g, yield 96%).

[0803] 1 H NMR (400MHz, DMSO-d6) δ6.84 (d, J=3.6Hz, 1H), 6.55-6.50 (m, 1H), 2.78-2.70 (m, 2H), 1.66-1.58 (m, 2H), 1.45-1.30 (m, 2H), 0.92 (t, J=7.2Hz, 1H).

[0804] 2. Synthesis of compound T1-3

[0805]

[0806] TI-2 (2.50 g, 11.41 mmol) was added to the reaction flask and dissolved in tetrahydrofuran (40 mL). The mixture was purged with nitrogen three times, and then the reaction system was cooled to -78 °C. LDA (1 N, 11 mL, 11.41 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for one hour, followed by the addition of methanol (7.5 mL). After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5%) to give a colorless oily compound T1-3 (2.00 g, yield 80%).

[0807] 1 H NMR (400MHz, DMSO-d6) δ7.00 (d, J=1.6Hz, 1H), 6.70 (dd, J=1.2, 2.4Hz, 1H), 2. 83-2.69 (m, 2H), 1.70-1.58 (m, 2H), 1.45-1.32 (m, 2H), 0.93 (t, J=7.6Hz, 1H).

[0808] 3. Synthesis of compound T1-4

[0809]

[0810] T1-3 (700 mg, 2.92 mmol) was added to a reaction flask and dissolved in NMP (10 mL), followed by Zn(CN)2 (343 mg, 2.92 mmol) and Pd(PPh3)4 (6.75 mg, 5.84 mmol). The reaction mixture was placed in a microwave reactor and heated to 80 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10%) to give a colorless oily compound T1-4 (350 mg, yield 73%). ESI [M+H] + =183.2.

[0811] 4. Synthesis of compound T1-5

[0812]

[0813] T1-4 (300 mg, 1.82 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (10 mL). Then, BH3·THF (1 N, 4 mL, 3.63 mmol) was added to the reaction system. After the addition was complete, the mixture was stirred at 60 °C for two hours. After the reaction was complete, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 50%) to give a colorless oily compound T1-5 (200 mg, yield 65%). ESI [M-16] + =153.3.

[0814] 5. Synthesis of Compound 110-3

[0815] Compound 110-3 was synthesized according to Example 1.

[0816] 6. Synthesis of compound 3-1-12

[0817]

[0818] 110-3 (408, 2.48 mmol) was added to a reaction flask and dissolved in dichloromethane (40 mL). Triethylamine (1.00 g, 9.92 mmol) and CDI (402 mg, 2.48 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. T1-5 (420 mg, 2.48 mmol) was then added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification was performed by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse-phase chromatography to obtain a white solid 3-1-12 (210 mg, yield: 24%). MS Calcd.: 360.3 [M+H] + MS Found: 359.9 [M+H] + .

[0819] 1H NMR (400MHz, DMSO-d6) δ7.08 (d, J=7.6Hz, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 6.8 1(d, J=8.0Hz, 1H), 6.71(s, 1H), 6.32(t, J=6.0Hz, 1H), 6.22(t, J=6.0Hz, 1H), 4.23 (d, J=6.0Hz, 2H), 4.11 (d, J=6.0Hz, 2H), 2.73 (t, J=7.6Hz, 2H), 2.60 (s, 6 H), 2.25 (s, 3H), 1.62-1.50 (m, 2H), 1.40-1.27 (m, 2H), 0.89 (t, J=7.6Hz, 3H).

[0820] Example 52: Preparation of compound 3-1-13 of the present invention

[0821]

[0822] 1. Synthesis of compound T4-6

[0823]

[0824] T4-5 (2.8 g, 20.0 mmol) was added to a reaction flask and dissolved in acetic acid (100 mL). Then, bromine (9.6 g, 60 mmol) was slowly added to the reaction system. After the addition was complete, the mixture was stirred at 65 °C for 2 days. After the reaction was complete, the mixture was diluted with ice water (300 mL), the bromine was destroyed by sodium thiosulfate, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was subjected to silica gel column chromatography (petroleum ether) to give a colorless oily compound T4-6 (5.0 g, yield 66%).

[0825] 2. Synthesis of compound T4-2

[0826]

[0827] T4-6 (2.5 g, 6.7 mmol) was added to the reaction flask and dissolved in THF (100 mL). The mixture was purged with nitrogen three times, and then the reaction system was cooled to -78 °C. 2.5 N n-butyllithium (5.4 mL, 13.4 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 4 hours. After the reaction was complete, a saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether) to give a colorless oily compound T4-2 (500 mg, yield 34%).

[0828] 3. Synthesis of compound T4-3

[0829]

[0830] T4-2 (500 mg, 2.3 mmol) was added to a reaction flask and dissolved in NMP (10 mL), followed by Zn(CN)2 (538 mg, 4.6 mmol) and Pd(PPh3)4 (265 mg, 0.23 mmol). The reaction mixture was placed in a microwave reactor and heated to 150 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5%) to give a pale yellow oily compound T4-3 (500 mg, 100% yield).

[0831] 4. Synthesis of compound T4-4

[0832]

[0833] T4-3 (500 mg, 3.03 mmol) was added to the reaction flask and dissolved in THF (20 mL). Then, 2.5 N lithium aluminum hydride (2.4 mL, 6.06 mmol) was added to the reaction system at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete, water (1 mL), 15% NaOH solution (1 mL), and water (3 mL) were added sequentially. The mixture was stirred for 30 minutes, then anhydrous magnesium sulfate was added and dried. The mixture was filtered, and the solvent was removed from the filtrate by vacuum distillation. The crude product was subjected to silica gel column chromatography (methanol / dichloromethane = 5%) to give a pale yellow oily compound T4-4 (110 mg, yield 21.6%).

[0834] 5. Synthesis of Compound 110-3

[0835] Compound 110-3 was synthesized according to Example 1.

[0836] 6. Synthesis of compound 3-1-13

[0837]

[0838] Add 110-3 (107 mg, 0.65 mmol) to a reaction flask, dissolve in dichloromethane (10 mL), then add triethylamine (197 mg, 1.95 mmol) and CDI (116 mg, 0.72 mmol) to the reaction system, and stir at room temperature for two hours; then add T4-4 (110 mg, 0.65 mmol), and stir at room temperature overnight. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse-phase preparative chromatography to obtain a white solid 3-1-13 (116.36 mg, yield: 50%). MS Calcd.: 360.3 [M+H] + MS Found: 360.2 [M+H] + .

[0839] 1 H NMR (400MHz, DMSO-d6) δ7.17 (d, J=3.2Hz, 1H), 7.11 (d, J=4.4Hz, 1H), 7.09 (s, 1H), 6.89 (s, 1H), 6.81 (d, J=7.6Hz, 1H), 6.26-6.20 (m, 2H), 4.23 (d , J=6.0Hz, 2H), 4.15 (d, J=5.6Hz, 2H), 2.59 (s, 6H), 2.51-2.49 (m, 2H), 2 .25(s, 3H), 1.58-1.50(m, 2H), 1.36-1.31(m, 2H), 0.90(t, J=7.2Hz, 3H).

[0840] Example 53: Preparation of compound 3-1-14 of the present invention

[0841]

[0842] 1. Synthesis of compound T7-2

[0843]

[0844] T7-1 (1.96 g, 10 mmol) was added to a reaction flask and dissolved in THF (50 mL). 60% NaH (1.0 g, 25 mmol) was added in portions to the reaction mixture at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 3 hours. Iodomethane (3.55 g, 25 mmol) was then added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10%) to give a pale yellow oily compound T7-2 (~1.5 g, yield 67%).

[0845] 2. Synthesis of compound T7-5

[0846]

[0847] T7-2 (896 mg, 4 mmol) was added to the reaction flask and dissolved in DOX / H2O (50 / 10 mL). SM-13 (612 mg, 6 mmol), potassium carbonate (1.1 g, 8 mmol), and Pd(PPh2)Cl2 (292 mg, 0.4 mmol) were added sequentially to the reaction mixture. After the additions were complete, the mixture was heated to 100 °C and stirred overnight. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation. The crude product was subjected to silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10%) to give a pale yellow oily compound T7-5 (~500 mg, yield 62%). MS Calcd.: 203.3 [M+H] + MS Found: 203.2 [M+H] + .

[0848] 3. Synthesis of compound T7-4

[0849]

[0850] T7-5 (500 mg, 2.5 mmol) was added to a reaction flask and dissolved in THF (20 mL). Then, 2.5N lithium aluminum hydride (2.0 mL, 5.0 mmol) was added to the reaction system at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete, water (1 mL), 15% NaOH solution (1 mL), and water (3 mL) were added sequentially. The mixture was stirred for 30 minutes, then anhydrous magnesium sulfate (20 g) was added and dried. The mixture was filtered, and the solvent was removed from the filtrate by vacuum distillation. The crude product was subjected to silica gel column chromatography (methanol / dichloromethane = 5%) to give a pale yellow oily compound T7-4 (280 mg, yield 53%). MS Calcd.: 207.2 [M+H] + MS Found: 207.3 [M+H] + .

[0851] 4. Synthesis of compound 3-1-14

[0852]

[0853] T7-4 (280 mg, 1.36 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (550 mg, 5.44 mmol) and CDI (221 mg, 1.36 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. SM-1 (154 mg, 1.36 mmol) was then added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification was performed by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse-phase chromatography to obtain a white solid 3-1-14 (125.06 mg, yield: 27%). MS Calcd.: 346.2 [M+H] + MS Found: 346.2 [M+H] + .

[0854] 1 H NMR (400MHz, DMSO-d6) δ7.47 (dd, J=2.8, 5.2Hz, 1H), 7.23 (s, 1H), 7.10 (d, J=8. 0Hz, 1H), 7.02 (d, J=4.8Hz, 1H), 6.89 (s, 1H), 6.82 (d, J=7.6Hz, 1H), 6.36 (t, J= 5.6Hz, 1H), 6.24 (t, J=5.6Hz, 1H), 4.22 (dd, J=6.0, 12.4Hz, 4H), 2.60 (s, 6H), 2 .54-2.50 (m, 2H), 1.56-1.48 (m, 2H), 1.33-1.27 (m, 2H), 0.89 (t, J=7.2Hz, 3H).

[0855] Example 54: Preparation of compound 3-1-15 of the present invention

[0856]

[0857] 1. Synthesis of Compound 163-2

[0858]

[0859] To a 250 mL reaction flask, add 163-1 (1.0 g, 7.41 mmol) and piperidine (10 mL), and stir overnight at 80 °C. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal column chromatography [petroleum ether:ethyl acetate (100:1-10:1)] to give a brownish-yellow oil, 163-2 (1.2 g, yield: 81%). MS Calcd.: 201.1 [M+H] + MS Found: 201.4 [M+H] + .

[0860] 2. Synthesis of Compound 163-3

[0861]

[0862] Add 163-2 (602 mg, 3.01 mmol) and Et2O (20 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0 °C under nitrogen atmosphere. Then add LAH (2.5 N in THF, 2.4 mL) and stir overnight at room temperature. After the reaction is complete, slowly add water (1 mL), 15% NaOH (3 mL), and water (3 mL), stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter, remove solvent by vacuum distillation to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol 20:1] to obtain yellow oil 163-3 (2.0 g, 61% yield).

[0863] 3. Synthesis of compound 3-1-15

[0864]

[0865] 163-3 (220 mg, 1.08 mmol) was added to a reaction flask and dissolved in dichloromethane (6 mL). Triethylamine (436 mg, 4.32 mmol) and CDI (262 mg, 1.62 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-1 (122 mg, 1.08 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared by reverse chromatography to give a white solid 3-1-15 (125.06 mg, 34%). MS Calcd.: 344.2 [M+H] + MS Found: 344.4 [M+H] + .

[0866] 1 H NMR (400MHz, DMSO-d6) δ: 7.47 (dd, J=4.8, 2.8Hz, 1H), 7.23 (dd, J=2.4, 0.8Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 7.03-7.00 (m, 1H), 6 .89 (s, 1H), 6.81 (d, J=8.0Hz, 1H), 6.37 (t, J=6.0Hz, 1H), 6.23 (t, J=5.6Hz, 1H), 4.24-4.20 (m, 4H), 2.60 (s, 6H), 2.25 (s, 3H).

[0867] Example 55: Preparation of compound 3-1-16 of the present invention

[0868]

[0869] 1. Synthesis of compound 23-A1-3

[0870]

[0871] 23-Al-5 (2.0 g, 14.8 mmol) and diethylamine (4.32 g, 59.2 mmol) were added to a reaction tube and dissolved in methylpyrrolidone (50 mL). The reaction mixture was stirred overnight at 140 °C. After the reaction was complete, it was cooled to room temperature, and water (50 mL) was slowly added to the reaction mixture. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 12%) to give a pale yellow oily 23-Al-3 (1.1 g, yield: 40%). MS Calcd.: 189.1 [M+H] + MS Found: 189.4 [M+H] + .

[0872] 2. Synthesis of compound 23-A1-4

[0873]

[0874] 23-Al-3 (1.1 g, 5.85 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (50 mL). 2.5 N lithium aluminum hydride (4.7 mL, 11.7 mmol) was added to the reaction system at 0 °C, and the mixture was stirred overnight at room temperature. After the reaction was complete, water (1 mL), 15% NaOH (1 mL), and water (3 mL) were slowly added to the reaction solution. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by normal column chromatography [dichloromethane:methanol (0%–15%)] to give a pale yellow oily 23-Al-4 (400 mg, yield: 36%). MS Calcd.: 193.2 [M+H] + MS Found: 193.3 [M+H] + .

[0875] 3. Synthesis of compound 3-1-16

[0876]

[0877] SM-1 (237 mg, 2.08 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (822 mg, 104 mmol) and CDI (337 mg, 2.08 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. Next, 23-Al-4 (400 mg, 2.08 mmol) was added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and preparative liquid chromatography yielded a white solid 3-1-16 (134.70 mg, yield: 20%). MS Calcd.: 332.2 [M+H] + MS Found: 332.2 [M+H] + .

[0878] 1H NMR (400MHz, DMSO-d6) δ7.47 (dd, J=2.8, 4.8Hz, 1H), 7.23 (dd, J=1.2, 2.8Hz, 1H) , 7.10 (d, J=7.6Hz, 1H), 7.02 (dd, J=1.2, 5.2Hz, 1H), 6.94 (s, 1H), 6.85 (dd, J=0. 8, 8.0Hz, 1H), 6.35 (t, J=6.0Hz, 1H), 6.16 (t, J=5.6Hz, 1H), 4.24 (d, J=5.6Hz, 2H ), 4.20 (d, J=6.0Hz, 2H), 2.93-2.87 (m, 4H), 2.26 (s, 3H), 0.90 (t, J=7.2Hz, 6H).

[0879] Example 56: Preparation of compound 3-1-17 of the present invention

[0880]

[0881] 1. Synthesis of compound 199-7

[0882]

[0883] SM-14 (2.0 g, 10.0 mmol) was added to a reaction flask and dissolved in toluene / water (40 mL / 8 mL). Then, 199-0 (3.0 g, 12.0 mmol), Cs₂CO₃ (9.78 g, 30.0 mmol), and Pd(dppf)Cl₂.DCM (82 mg, 0.1 mmol) were added sequentially. The mixture was purged three times with nitrogen and stirred overnight at 80 °C under nitrogen atmosphere. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was poured into water and extracted three times with ethyl acetate (100 mL). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oil 199-7 (1.5 g, yield: 47%). MS Calcd.: 265.1 [M+H] + MS Found: 265.4 [M+H] + .

[0884] 2. Synthesis of compound 199-8

[0885]

[0886] To a 250 mL sealed tube, add 199-7 (1.5 g, 5.68 mmol) and dimethylaminetetrahydrofuran (60 mL), and stir at 70 °C for two days. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then purified by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oily substance 199-8 (1.3 g, yield: 79%). MS Calcd.: 290.1 ​​[M+H] + MS Found: 290.4 [M+H] + .

[0887] 3. Synthesis of compound 199-4

[0888]

[0889] Add 199-8 (600 mg, 2.08 mmol) to a reaction flask, dissolve in dichloromethane (10 mL), and add trifluoroacetic acid (2 mL) dropwise at room temperature. After the addition is complete, react at room temperature for one hour. After the reaction is complete, evaporate the solvent under reduced pressure to obtain the residue. Dissolve the residue in dichloromethane and pour into water. Adjust the pH to 9 with saturated sodium bicarbonate solution. Extract three times with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain the residue. Purify the residue by normal column chromatography [dichloromethane:methanol (100:1-5:1)] to give a yellow oily substance 199-4 (200 mg, yield: 51%). MS Calcd.: 190.1 [M+H] + MS Found: 190.2 [M+H] + .

[0890] 4. Synthesis of compound 199-5

[0891]

[0892] SM-15 (200 mg, 1.06 mmol) was added to a reaction flask and dissolved in DMF (5 mL). Then, 199-4 (162 mg, 1.59 mmol), DIPEA (410 mg, 3.18 mmol), and EDCI (305 mg, 1.59 mmol) were added sequentially. The reaction was carried out under nitrogen atmosphere with stirring at room temperature for two hours. HOBT (215 mg, 1.59 mmol) was then added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted three times with ethyl acetate (5 mL). The organic phase was washed twice with water and once with saturated brine (5 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give a yellow oily substance 199-5 (60 mg, yield: 30%). MS Calcd.: 161.1 [M+H] +MS Found: 161.4 [M+H] + .

[0893] 5. Synthesis of compound 199-6

[0894]

[0895] 199-5 (3.0 g, 22.73 mmol) was added to an autoclave, dissolved in methanol (100 mL), and then Raney-Ni (7.2 g, 113.65 mmol) was added. The mixture was purged three times with hydrogen, and the reaction was carried out overnight at room temperature under hydrogen atmosphere with stirring. After the reaction was complete, the mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by normal column chromatography [dichloromethane:methanol (20:1-5:1)] to give a yellow oil, 199-6 (3.2 g, yield: 89.9%). MS Calcd.: 278.2 [M+H] + MS Found: 278.4 [M+H] + .

[0896] 6. Synthesis of compound 3-1-17

[0897]

[0898] SM-1 (25 mg, 0.22 mmol) was added to a reaction flask and dissolved in dichloromethane (3 mL). Triethylamine (87.5 mg, 0.87 mmol) and CDI (53.5 mg, 0.33 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. 199-6 (60 mg, 0.22 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification was achieved by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse chromatography to obtain a white solid 3-1-17 (18.32 mg, 20%). MS Calcd.: 417.1 [M+H] + MS Found: 417.3 [M+H] + .

[0899] 1H NMR (400MHz, DMSO-d6) δ: 7.96 (t, J=5.6Hz, 1H), 7.47 (q, J=3.2Hz, 1H), 7.23 (d, J=5 .6Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 7.03 (t, J=4.4Hz, 1H), 6.89 (s, 1H), 6.84 (q, J=8.0 Hz, 1H), 6.40 (t, J=6.0Hz, 1H), 6.28 (t, J=6.0Hz, 1H), 4.61-4.55 (m, 4H), 4.25-4.2 0 (m, 4H), 3.72-3.67 (m, 1H), 3.31-3.25 (m, 2H), 2.67 (t, J=7.2Hz, 2H), 2.60 (s, 6H).

[0900] Example 57: Preparation of compound 3-1-18 of the present invention

[0901]

[0902] 1. Synthesis of Compound 125-1

[0903]

[0904] 110-1 (3.0 g, 22.2 mmol) was added to a reaction flask and dissolved in 100 mL of 2N methylamine. The mixture was stirred overnight at 70 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was purified by normal column chromatography [petroleum ether:ethyl acetate 5:1] to give a yellow solid 125-1 (3.0 g, yield: 94%). MS Calcd.: 147.1 [M+H] + MS Found: 147.3 [M+H] +

[0905] 2. Synthesis of Compound 125-2

[0906]

[0907] 125-1 (1.0 g, 6.85 mmol) and diethyl ether (20 mL) were added to a reaction flask. Lithium aluminum hydride (13.70 mmol) was added to the system at 0 °C, and the mixture was stirred overnight at room temperature. After the reaction was complete, water (1 mL), 15% sodium hydroxide (1 mL), and water (3 mL) were slowly added, and the mixture was stirred at room temperature for 20 minutes. The mixture was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by normal column chromatography [dichloromethane:methanol 20:1] to give a yellow solid 125-2 (600 mg, 58% yield).

[0908] 3. Synthesis of compound 3-1-18

[0909]

[0910] SM-1 (220 mg, 1.95 mmol) and dichloromethane (20 mL) were added to a reaction flask. Then, CDI (473 mg, 2.92 mmol) and triethylamine (591 mg, 5.85 mmol) were added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by preparative liquid chromatography to give a white solid 3-1-18 (116 mg, 20% yield). MS Calcd.: 290.1 ​​[M+H] + MS Found: 290.4 [M+H] + .

[0911] 1 H NMR (400MHz, DMSO-d6) δ: 7.44 (q, J=2.8Hz, 1H), 7.19 (q, J=1.2Hz, 1H), 6.98 (dd, J=1.2, 4.8Hz, 1H), 6.34-6.27 (m, 3H), 6.8 4(d, J=7.2Hz, 1H), 5.52 (d, J=4.8Hz, 1H), 4.17 (d, J=5.6Hz, 2H), 4.02 (d, J=6.0Hz, 2H), 2.66 (d, J=5.2Hz, 3H), 2.18 (s, 3H).

[0912] Example 58: Preparation of compound 3-1-19 of the present invention

[0913]

[0914] 1. Synthesis of 140-3

[0915] Compound 140-3 was synthesized according to Example 18.

[0916] 2. Synthesis of 3-1-19

[0917] CDI (1751.44 mg, 10.811 mmol) was added to a tetrahydrofuran (10 mL) solution containing compound SM-12 (350 mg, 3.604 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, compound 140-3 (1183.84 mg, 7.208 mmol) and 2-[ethyl(2-hydroxyethyl)amino]ethanol-1-ol (2 mL, 15.256 mmol) were added, and the mixture was stirred at 80 °C for 14 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (20 mL x 3), washed with concentrated brine, dried over anhydrous Na₂SO₄, concentrated under vacuum, and purified by preparative liquid chromatography to give a white solid compound 3-1-19 (157.5 mg, yield 15.21%). MS Calcd.: 288.4 [M+H] + MS Found: 288.2 [M+H] + .

[0918] 1 H NMR (400MHz, DMSO-d6) δ11.73 (s, 1H), 7.06-7.04 (m, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 6.80-6.7 9(m, 2H), 6.46-6.43(m, 1H), 6.32-6.30(m, 1H), 4.22-4.15(m, 4H), 2.60(s, 6H), 2.21(s, 3H).

[0919] Example 59: Preparation of compound 3-1-20 of the present invention

[0920]

[0921] 1. Synthesis of 280-3

[0922] Compound 280-3 was synthesized according to Example 13.

[0923] 2. Synthesis of 3-1-20

[0924] CDI (3.24 g, 19.971 mmol) was added to a 20 mL solution of tetrahydrofuran containing compound 280-3 (1.94 g, 19.971 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, compound SM-12 (1.5 g, 9.985 mmol) and 2-[ethyl(2-hydroxyethyl)amino]ethanol-1-ol (2 mL, 15.256 mmol) were added, and the mixture was stirred at 80 °C for 14 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (20 mL x 3), washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography to give a white solid compound 3-1-20 (269.1 mg, yield, 9.86%). MS Calcd.: 274.3 [M+H] + MS Found: 274.1 [M+H] + .

[0925] 1 H NMR (400MHz, DMSO-d6) δ11.82 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8Hz, 1H), 7.43-7.41 (m, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 6.82-6.75 (m, 2H), 4.27 (d, J=8Hz, 2H), 2.55 (s, 6H), 2.21 (s, 3H).

[0926] Example 60: Preparation of compound 3-1-21 of the present invention

[0927]

[0928] 1. Synthesis of 280-3

[0929] Compound 280-3 was synthesized according to Example 13.

[0930] 1. Synthesis of 3-1-21

[0931] SM-7 (300 mg, 2.00 mmol) and triethylamine (606 mg, 5.99 mmol) were added to a reaction flask and dissolved in dichloromethane (10 mL). The mixture was cooled to 0°C in an ice-water bath, and CDI (356 mg, 2.20 mmol) was added and stirred for 30 minutes. Then, 280-3 (330 mg, 2.20 mmol) was slowly added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 50%) and reverse-phase chromatography to obtain a white solid 3-1-21 (89 mg, yield: 15%). MS Calcd.: 291.1 [M+H] +MS Found: 291.2 [M+H] + .

[0932] 1 H NMR (400MHz, DMSO-d6) δ8.44 (d, J=1.6Hz, 1H), 8.03 (s, 1H), 7.88 (d, J=8.0Hz, 1H), 7.67 (t, J=5.6Hz, 1 H), 7.28 (s, 1H), 6.94 (s, 1H), 6.79 (d, J=8.4Hz, 1H), 4.59 (d, J=5.6Hz, 2H), 2.56 (s, 6H), 2.22 (s, 3H).

[0933] Example 61: Preparation of compound 3-1-22 of the present invention

[0934]

[0935] 1. Synthesis of compound 110-3

[0936] Compound 110-3 was synthesized according to Example 1.

[0937] 2. Synthesis of compound 3-1-22

[0938] SM-10 (408 mg, 3.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.52 g, 15.0 mmol) and CDI (486 mg, 3.0 mmol) were added to the reaction system, and the mixture was stirred at room temperature for two hours. Then, 110-3 (492 mg, 3.0 mmol) was added to the system, and the mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) and preparative liquid chromatography to obtain an off-white solid 3-1-22 (116.23 mg, yield: 13%). MS Calcd.: 291.1 [M+H] + MS Found: 291.1 [M+H] + .

[0939] 1 H NMR (400MHz, DMSO-d6) δ8.10 (d, J=2.0Hz, 1H), 7.11-7.09 (m, 2H), 6.94 (s, 1H), 6.84 (d , J=7.6Hz, 1H), 6.72 (d, J=1.6Hz, 1H), 4.36 (d, J=5.6Hz, 2H), 2.63 (s, 6H), 2.26 (s, 3H).

[0940] Example 62: Preparation of compound 3-1-23 of the present invention

[0941]

[0942] 1. Synthesis of compound 110-3

[0943] Compound 110-3 was synthesized according to Example 1.

[0944] 2. Synthesis of compound 3-1-23

[0945] 110-3 (820 mg, 5.0 mmol, 1.0 equiv.) and SM-16 (765 mg, 5.0 mmol, 1.0 equiv.) were dissolved in DCM (15.0 mL) and reacted at room temperature for 2 hours. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) gave a white solid compound 3-1-23 (289 mg, 0.97 mmol, 19% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd forC 18 H 23 N3OH + 298.1914; Found 298.1913.

[0946] 1 H NMR (400MHz, CDCl3): δ7.31-7.18(m, 3H), 7.14(d, J=7.6Hz, 1H), 6.93-6.83(m , 2H), 5.81(s, 1H), 5.39(s, 1H), 4.35-4.29(m, 4H), 2.52(s, 6H), 2.30(s, 3H). 13 C NMR (100MHz, CDCl3): δ158.60, 151.63, 139.51, 138.04, 130.25, 129.77, 128.50, 127.37, 127.10, 124.81, 120.04, 45.03, 44.53, 40.72, 21.30.

[0947] Example 63: Preparation of compound 3-1-24 of the present invention

[0948]

[0949] 1. Synthesis of compound 02-2

[0950]

[0951] O2-1 (3.94 g, 30 mmol, 1.0 equiv.) was dissolved in Et2O (60 mL), and lithium aluminum hydride (2.85 g, 75 mmol, 2.5 equiv.) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, 3 mL of 15% NaOH solution was added to quench the reaction, followed by the addition of 3 mL of water, and then another 3 mL of 15% NaOH solution. The mixture was filtered through diatomaceous earth and anhydrous Na2SO4, and concentrated under reduced pressure to obtain a yellow oily compound O2-2 (3.74 g, 92% yield).

[0952] 2. Synthesis of compound 02-3

[0953]

[0954] After dissolving 02-2 (270 mg, 2.0 mmol) in Toluene (12 mL), Triphosgene (297 mg, 1.0 mmol) was added. After the addition was complete, the mixture was refluxed at 120 °C for 4 h. The toluene was then evaporated to dryness. The resulting yellow oily crude product 02-3 was used directly in the next step.

[0955] 3. Synthesis of compound 110-3

[0956] Compound 110-3 was synthesized according to Example 1.

[0957] 4. Synthesis of compound 3-1-24

[0958]

[0959] 110-3 (164 mg, 1.0 mmol) and O2-3 (161 mg, 1.0 mmol) were dissolved in DCM (6.0 mL) and reacted at room temperature for 1 h. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) gave a yellow solid compound 3-1-24 (50 mg, 15% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 27 N3OH + 326.2227; Found 326.2229.

[0960] 1H NMR (400MHz, CDCl3): δ7.16 (d, J=7.6Hz, 1H), 6.91-6.84 (m, 3H), 6.81 (s, 2H), 5.61 (s, 1H) , 5.30 (s, 1H), 4.33 (s, 2H), 4.27 (d, J = 5.6Hz, 2H), 2.54 (s, 6H), 2.31 (s, 3H), 2.26 (s, 6H).

[0961] Example 64: Preparation of compound 3-1-25 of the present invention

[0962]

[0963] 1. Synthesis of compound 110-3

[0964] Compound 110-3 was synthesized according to Example 1.

[0965] 2. Synthesis of compound 110-3-2

[0966]

[0967] 110-3-1 (1.01 g, 5 mmol) was dissolved in DCM (30 mL), and 110-3 (820 mg, 5 mmol) was slowly added dropwise at -10 °C. After the addition was complete, the reaction was continued at -10 °C for 16 h. After the reaction was complete, water was added to quench the reaction, and then DCM was added to dilute the mixture. The mixture was washed twice with a 20% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid compound 110-3-2 (1.06 g, 65% yield).

[0968] 1 H NMR (400MHz, CDCl3) δ8.21 (m, 2H), 7.30 (m, 2H), 7.18 (d, J = 7.6Hz, 1H), 7.00 (d, J = 1.7Hz, 1H), 6.9 0 (dd, J=7.8, 1.7Hz, 1H), 6.41 (t, J=6.0Hz, 1H), 4.51 (d, J=5.7Hz, 2H), 2.72 (s, 6H), 2.34 (s, 3H).

[0969] 3. Synthesis of compound 3-1-25

[0970]

[0971] 110-3-2 (592 mg, 1.8 mmol) and SM-24 (268 mg, 2 mmol) were dissolved in 1,4-dioxane (10 mL), and DIPEA (626 μL, 3.6 mmol) was added. The mixture was reacted in an oil bath at 65 °C for 16 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) gave a white solid compound 3-1-25 (151 mg, 30% yield). HRMS (ESI-TOF) m / z: [M+H]+ Calcd for C 15 H 22 N5O + 288.1819; Found 288.1824.

[0972] 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 7.40 (d, J=1.9Hz, 1H), 7.15 (d, J=7.7Hz, 1H), 6.92 (m, 3H), 6. 13 (d, J=1.9Hz, 1H), 4.86 (d, J=4.9Hz, 2H), 4.30 (s, 2H), 3.70 (s, 3H), 2.42 (s, 6H), 2.32 (s, 3H).

[0973] Example 65: Preparation of compound 3-1-26 of the present invention

[0974]

[0975] 1. Synthesis of compound 110-3-2

[0976] Compound 110-3-2 was synthesized according to Example 59.

[0977] 2. Synthesis of compound 3-1-26

[0978] 110-3-2 (201 mg, 1.5 mmol) and SM-25 (222 mg, 2 mmol) were dissolved in 1,4-dioxane (10 mL), and triethylamine (404 mg, 4 mmol) was added. The reaction was carried out at 50 °C for 4 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) gave a white solid compound (300 mg, 50% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 24 N5O + 302.1975; Found 302.1977.

[0979] 1H NMR (400MHz, CDCl3) δ7.35 (t, J=1.6Hz, 1H), 7.14 (d, J=7.7Hz, 1H), 6.88 (d, J=7.4Hz, 2H), 6.06 (t, J=1.7Hz, 1H), 5.34 (s, 1H), 4.36 (dd, J=5.5, 3.3Hz, 2H), 4.26 (d, J=5.8Hz, 2H), 3.69 (d, J=1.8Hz, 3H), 2.53 (s, 6H), 2.31 (s, 3H).

[0980] Example 66: Preparation of compound 3-2-1 of the present invention

[0981]

[0982] 1. Synthesis of compound 110-3

[0983] Compound 110-3 was synthesized according to Example 1.

[0984] 2. Synthesis of compound 3-2-1

[0985] SM-7 (550 mg, 4.82 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.46 g, 14.47 mmol) and TCDI (858 mg, 4.82 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. 110-3 (790 mg, 4.82 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to give a pale yellow solid 3-2-1 (550 mg, yield: 37%). MS Calcd.: 321.1 [M+H] + MS Found: 3214 [M+H] + .

[0986] 1 H NMR (400MHz, DMSO-d6) δ: 8.34 (d, J = 1.4Hz, 1H), 7.22-7.12 (m, 2H), 6.95 (d, J = 9.2Hz , 1H), 6.90-6.85(m, 1H), 5.10(s, 2H), 4.83-4.72(m, 2H), 2.67(s, 6H), 2.29(s, 3H).

[0987] Example 67: Preparation of compound 3-2-2 of the present invention

[0988]

[0989] 1. Synthesis of compound 110-3

[0990] Compound 110-3 was synthesized according to Example 1.

[0991] 2. Synthesis of compound 3-2-2

[0992] SM-5 (500 mg, 4.39 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.33 g, 13.16 mmol) and TCDI (781 mg, 4.39 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. 110-3 (720 mg, 4.39 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to give a pale yellow solid 3-2-2 (405 mg, yield: 29%). MS Calcd.: 320.1 [M+H] + MS Found: 320.4 [M+H] + .

[0993] 1 H NMR (400MHz, CD3OD) δ7.35 (dd, J=0.8, 4.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.06 (s, 1H), 7.02 ( d, J=3.2Hz, 1H), 6.97 (q, J=5.2Hz, 2H), 4.57 (s, 2H), 4.34 (s, 2H), 2.63 (s, 6H), 2.32 (s, 1H).

[0994] Example 68: Preparation of compound 3-2-3 of the present invention

[0995]

[0996] 1. Synthesis of compound 110-3

[0997] Compound 110-3 was synthesized according to Example 1.

[0998] 2. Synthesis of compound INT-1

[0999]

[1000] 110-3 (1.64 g, 10 mmol) was dissolved in ethanol (20 mL), and carbon disulfide (1.81 mL, 30 mmol) and triethylamine (1.39 mL, 10 mmol) were added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 1 hour. Then, DMAP (37 mg, 0.3 mmol) and Boc2O (2.3 mL, 10 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 40:1) to give a yellow oily compound INT-1 (824 mg, 67% yield).

[1001] 2. Synthesis of compound 3-2-3

[1002]

[1003] INT1 (237 mg, 1.15 mmol) and SM-7 (174 mg, 1.15 mmol) were dissolved in toluene (3 mL), and the reaction was carried out overnight at room temperature. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) gave a yellow oily compound 3-2-3 (210 mg, 57% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 20 N4S2H + 321.1203; Found 321.1207.

[1004] 1 H NMR (400MHz, CDCl3) δ8.32 (d, J=1.2Hz, 1H), 7.11 (d, J=7.6Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.83 (d, J=7.6Hz, 1H), 6.42 (s, 1H), 6.16 (s, 1H), 5.05 (d, J=5.8Hz, 2H), 4.48 (s, 1H), 2.66 (s, 6H), 2.29 (s, 3H).

[1005] Example 69: Preparation of compound 3-2-4 of the present invention

[1006]

[1007] 1. Synthesis of compound SM-17

[1008]

[1009] SM-16 (1.77 mL, 20 mmol) was dissolved in EtOH (40 mL), and CS2 (3.61 mL, 60 mmol) and triethylamine (2.78 mL, 20 mmol) were added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 1 h. Then, DMAP (73 mg, 0.6 mmol) and Boc2O (4.6 mL, 20 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 40:1) to give a yellow oily compound SM-17 (2.35 g, 85% yield).

[1010] 2. Synthesis of Compound 110-3

[1011] Compound 110-3 was synthesized according to Example 1.

[1012] 3. Synthesis of compound 3-2-4

[1013]

[1014] 110-3 (247 mg, 1.5 mmol) and SM-17 (209 mg, 1.5 mmol) were dissolved in Toluene (4.5 mL), and the reaction was carried out at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) gave a white solid compound 3-2-4 (342 mg, 75% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N3OSH + 304.1479; Found 304.1471.

[1015] 1 H NMR (600MHz, CDCl3) δ7.37 (d, J=1.0Hz, 1H), 7.13 (d, J=7.8Hz, 1H), 6.95-6.91 (m, 2H), 6.34 (dd , J=3.2, 2.0Hz, 1H), 6.24 (d, J=3.0Hz, 1H), 4.78 (s, 2H), 4.30 (s, 2H), 2.56 (s, 6H), 2.32 (s, 3H).

[1016] Example 70: Preparation of compound 3-2-5 of the present invention

[1017]

[1018] 1. Synthesis of compound INT1

[1019] Compound INT1 was synthesized according to Example 63.

[1020] 2. Synthesis of compound 3-2-5

[1021] INT-1 (309 mg, 1.5 mmol) and SM-18 (200 mg, 1.5 mmol) were dissolved in Toluene (4.5 mL), and the reaction was carried out at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) gave a white solid compound 3-2-5 (170 mg, 40% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N3OSH + 304.1479; Found 304.1473.

[1022] 1 H NMR (400MHz, CDCl3) δ7.38 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=7.7Hz, 1H), 6.98-6 .86(m, 2H), 6.35(s, 1H), 4.58(s, 2H), 4.35(s, 2H), 2.52(s, 6H), 2.32(s, 3H).

[1023] Example 71: Preparation of compound 3-2-6 of the present invention

[1024]

[1025] 1. Synthesis of compound INT-1

[1026] Compound INT1 was synthesized according to Example 63.

[1027] 2. Synthesis of compound 3-2-6

[1028] SM-16 (107 mg, 1.1 mmol) was weighed into a 10 mL flask, and toluene (3 mL) and triethylamine (0.18 mL, 1.2 mmol) were added. The mixture was stirred at room temperature for 2 hours, and then INT-1 (206 mg, 1.0 mmol) was added. The reaction was stirred at room temperature for approximately 5 hours until the starting material was completely consumed. The reaction solution was purified by silica gel column chromatography (PE:EtOAC = 10:1-3:1) to give a white solid 3-2-6 (287 mg, 95% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 22 N3OS+ 304.1479; Found 304.1512.

[1029] 1 H NMR (400MHz, CDCl3) δ7.32 (dd, J=1.9, 0.9Hz, 1H), 7.11 (d, J=7.6Hz, 1H), 6.92 (d, J=1.8Hz, 1H), 6.84 (dd, J=7.7, 1.8Hz, 1H), 6.34-6.18 (m, 3H), 6.06 (s, 1H), 4.66 (d, J=5.3Hz, 2H), 4.58-4.42 (m, 2H), 2.67 (s, 6H), 2.29 (s, 3H).

[1030] Example 72: Preparation of compound 3-2-7 of the present invention

[1031]

[1032] 1. Synthesis of compound INT-1

[1033] Compound INT-1 was synthesized according to Example 63.

[1034] 2. Synthesis of compound 3-2-7

[1035] SM-18 (146 mg, 1.1 mmol) was weighed into a 10 mL flask, and toluene (3 mL) and triethylamine (0.18 mL, 1.2 mmol) were added. The mixture was stirred at room temperature for 2 hours, and then INT-1 (206 mg, 1.0 mmol) was added. The reaction was continued to be stirred at room temperature for approximately 5 hours. The reaction solution was directly purified by silica gel column chromatography (PE:EtOAc = 10:1-3:1 elution) to give a white solid 3-2-7 (287 mg, 95% yield). HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 16 H 21 N3NaOS + 326.1298; Found 326.1308.

[1036] 1H NMR (400MHz, CDCl3) δ7.36 (d, J=1.7Hz, 1H), 7.30 (s, 1H), 7.10 (d, J=7.6Hz, 1H), 6.90 (d, J=1.8Hz, 1H), 6.8 2 (dd, J=7.5, 1.8Hz, 1H), 6.38-6.14 (m, 2H), 5.95 (s, 1H), 4.48 (d, J=5.8Hz, 4H), 2.66 (s, 6H), 2.29 (s, 3H). 13 C NMR (101MHz, CDCl3) δ181.8, 153.3, 143.6, 140.2, 134.7, 131.7, 131.7, 121.4, 121.3, 117.6, 110.0, 48.5, 44.0, 39.8, 18.3.

[1037] Example 73: Preparation of compound 3-2-8 of the present invention

[1038]

[1039] 1. Synthesis of compound 110-3

[1040] Compound 110-3 was synthesized according to Example 1.

[1041] 2. Synthesis of compound INT10

[1042]

[1043] 110-3 (986 g, 6 mmol) was dissolved in anhydrous ethanol (12 mL), and carbon disulfide (1.1 mL, 18 mmol) and triethylamine (0.84 mL, 6 mmol) were added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 1 hour. Then, DMAP (22 mg, 0.18 mmol) and Boc2O (1.38 mL, 6 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 40:1) to give a yellow oily compound INT-10 (778 mg, 63% yield).

[1044] 3. Synthesis of compound 3-2-8

[1045]

[1046] INT-10 (412 mg, 2 mmol) and SM-33 (268 mg, 2 mmol) were dissolved in Toluene (4.5 mL), and triethylamine (404 mg, 4 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) gave a white solid compound 3-2-8: 150 mg, in 25% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N4OS + 305.1431; Found 305.1430.

[1047] 1 H NMR (400MHz, CDCl3) δ9.29 (s, 1H), 8.17 (d, J = 1.7Hz, 1H), 7.26 (s, 6H), 7.14 (d, J = 7.7Hz, 1H), 6.96 (d, J = 7. 6Hz, 2H), 6.84 (s, 1H), 6.16 (d, J=1.7Hz, 1H), 4.99 (d, J=5.5Hz, 2H), 4.31 (s, 2H), 2.66 (s, 6H), 2.33 (s, 3H).

[1048] Example 74: Preparation of compound 3-2-9 of the present invention

[1049]

[1050] 1. Synthesis of compound 110-3

[1051] Compound 110-3 was synthesized according to Example 1.

[1052] 2. Synthesis of 3-2-9

[1053] SM-12 (522 mg, 3.09 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (732 mg, 9.27 mmol) and TCDI (550 mg, 3.09 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. Next, 110-3 (506 mg, 3.09 mmol) was added to the system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol: 95:5], and further purified by preparative liquid chromatography to obtain an off-white solid 3-2-9 (105.25 mg, yield 11%). MS Calcd.: 304.2 [M+H] + MS Found: 304.3 [M+H] + .

[1054] 1 H NMR (400MHz, DMSO-d6), δ11.89 (s, 1H), 7.87 (br, 2H), 7.11 (d, J=7.6Hz, 1H), 7.02~6.83 (m, 4H), 4.65 (m, 4H), 2.59 (s, 6H), 2.26 (s, 3H).

[1055] Example 75: Preparation of compound 3-2-10 of the present invention

[1056]

[1057] 1. Synthesis of compound 3-2-9

[1058] Compound 3-2-9 was synthesized according to Example 74.

[1059] 2. Synthesis of compound INT-11

[1060]

[1061] 3-2-9 (350 mg, 1.16 mmol) was dissolved in tetrahydrofuran (20 mL) in a reaction flask. Triethylamine (351 mg, 3.40 mmol), DMAP (15 mg, 0.12 mmol), and (Boc)₂O (506 mg, 2.32 mmol) were added sequentially to the system, and the mixture was stirred overnight at 70 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] to obtain INT-11 (410 mg, yield 88%). MS Calcd.: 404.2 [M+H] + MS Found: 404.3 [M+H] + .

[1062] 3. Synthesis of compound INT-12

[1063]

[1064] INT-11 (403 mg, 1.0 mmol) was added to a reaction tube and dissolved in acetonitrile (10 mL). Iodomethane (213 mg, 1.5 mmol) was then added, and the tube was sealed and stirred overnight at 40 °C. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1–2:1)] yielded a pale yellow solid, INT-12 (400 mg, yield: 95%). MS Calcd.: 417.2 [M+H] + MS Found: 417.8 [M+H] + .

[1065] 4. Synthesis of compound 3-2-10

[1066]

[1067] INT-12 (400 mg, 0.96 mmol) was added to a sealed tube, dissolved in acetonitrile (10 mL), and then ammonia (5 mL) was added. The mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was then subjected to column chromatography [dichloromethane:methanol (100:1-5:1)] to give a grayish-white solid 3-2-10 (106.86 mg, yield: 39%). MS Calcd.: 287.2 [M+H] + MS Found: 287.3 [M+H] + .

[1068] 1 H NMR (400MHz, CD3OD) δ: 7.21 (d, J=8.0Hz, 1H), 7.06 (s, 1H), 7.01 (s, 2H), 6.96 (d, J=7.6Hz, 1H), 4.42 (s, 2H), 4.35 (s, 2H), 2.61 (s, 6H), 2.32 (s, 3H).

[1069] Example 76: Preparation of compound 3-2-11 of the present invention (P3-2-9-2)

[1070]

[1071] 1. Synthesis of compound T7-4

[1072] Compound T7-4 was synthesized according to Example 53.

[1073] 2. Synthesis of compound T7-6

[1074]

[1075] At 0 °C, thiophosgene (0.44 mL, 5.7 mmol) was slowly added to a 10 mL solution of dichloromethane containing T7-4 (1 g, 5.2 mmol) and DIEA (1.7 mL, 10.4 mmol), and the mixture was stirred at room temperature for two hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain T7-6 (1.2 g, 98% yield).

[1076] 3. Synthesis of compound 3-2-11

[1077]

[1078] SM-1 (1.16 g, 10.2 mmol) and DIEA (2 mL) were added to a tetrahydrofuran solution (10 mL) containing T7-6 (1.2 g, 5.1 mmol). The mixture was stirred at 80 °C for 3 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain the crude product. After purification by column chromatography, a white solid 3-2-11 (331 mg, yield 19%) was given. LCMS: m / z calculated for [M+H] + 348.5, found 348.1.

[1079] 1 H NMR (400MHz, DMSO-d6) δ 7.94-7.76(m, 1H), 7.40-7.38(m, 1H), 7.11-7.84(m, 6H), 4.87-4.69(m, 4H), 2.71-2.52(m, 8H), 1.60-1.51(m, 2H), 0.90-0.87(m, 3H).

[1080] Example 77: Preparation of compound 3-2-12 of the present invention

[1081]

[1082] 1. Synthesis of A3-2

[1083]

[1084] At 0°C, potassium nitrate (5.6 g, 55.3 mmol) was added to 10 mL of a sulfuric acid solution containing compound A3-1 (10 g, 50.2 mmol) and stirred for 30 minutes. After the reaction was complete, the solution was concentrated under reduced pressure, 200 mL of water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give A3-2 (4 g, 33% yield).

[1085] 2. Synthesis of A3-3

[1086]

[1087] At 0 °C, zinc (5.36 g, 81.94 mmol) and ammonium chloride (5.26 g, 98.32 mmol) were added to a water / 2,6-dioxane solution (4 / 16 mL) containing compound A3-2 (4 g, 16.39 mmol), and the mixture was stirred for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure, 20 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give A3-3 (3.5 g, 99% yield). m / z calculated for [M+H] + 151.1, found 151.1.

[1088] 3. Synthesis of A3-4

[1089]

[1090] At 0 °C, acetic acid (0.94 mL, 16.35 mmol), paraformaldehyde (8.2 g, 81.74 mmol), and sodium borohydride (3.09 g, 81.74 mmol) were added to a methanol solution (35 mL) containing compound A3-3 (3.5 g, 16.35 mmol) and stirred for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure, 200 mL of water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give a yellow oily substance A3-4 (3.5 g, 88% yield). m / z calculated for [M+H] + 224.2, found 224.0.

[1091] 4. Synthesis of A3-5

[1092]

[1093] Under nitrogen protection, Zn(CN)₂ (5 g, 42.74 mmol), zinc (2.83 g, 43.36 mmol), Pd₂(dba)₃ (0.66 g, 0.72 mmol), Pd(dppf)Cl₂ (2.12 g, 2.89 mmol), and DMA (30 mL) were added to a methanol solution (35 mL) containing compound A3-4 (3.5 g, 14.45 mmol). The mixture was stirred at 150°C for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure, 200 mL of water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give a yellow oily substance A3-5 (2.7 g, 99% yield). m / z calculated for [M+H] + 189.3, found 189.1.

[1094] 5. Synthesis of A3-6

[1095]

[1096] Lithium aluminum tetrahydrofuran (14.45 mL) containing compound A3-5 (1.7 g, 9.03 mmol) was slowly added to a tetrahydrofuran solution (10 mL), and the mixture was stirred at 40°C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, 200 mL of water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give a yellow oily compound A3-6 (1.0 g, 58% yield). m / z calculated for [M+H] + 193.3, found 193.1.

[1097] 6. Synthesis of A3-7

[1098]

[1099] DIEA (1008.16 mg, 7.80 mmol) and thiophosgene (358.7 mg, 3.12 mmol) were added to a 10 mL solution of dichloromethane containing compound A3-6 (500 mg, 2.60 mmol), and the mixture was stirred for half an hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a black oily substance A3-7 (0.50 g, yield 82%). m / z calculated for [M+H] + 235.4, found 235.1.

[1100] 7. Synthesis of 3-2-12

[1101]

[1102] To a 10 mL solution of tetrahydrofuran containing compound A3-7 (500 mg, 2.13 mmol), DIEA (827.25 mg, 6.40 mmol) and thiophen-2-ylmethanamine (289.75 mg, 2.56 mmol) were added, and the mixture was stirred at room temperature for half an hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a white solid 3-2-12 (213 g, yield 28%). m / z calculated for [M+H] + 348.54, found 348.1.

[1103] 1HNMR (400MHz, DMSO-d6) δ7.90 (s, 2H), 7.47-7.30 (m, 1H), 7.13-7.09 (m, 1H), 7.04 (s, 1H), 7.02-6.99 (m, 1H), 6.97-6.93 (m, 1H), 6.91- 6.88(m, 1H), 4.91-4.81(m, 2H), 4.60(s, 2H), 2.64-2.59(m, 1H), 2.58(s, 6H), 2.56-2.55(m, 1H), 1.61-1.54(m, 2H), 0.94-0.90(m, 3H).

[1104] Example 78: Preparation of compound 3-2-13 of the present invention

[1105]

[1106] 13-3-1 (300 mg, 2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (606 mg, 6.0 mmol) and CDI (630 mg, 2.4 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, SM-5 (226 mg, 2.0 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography to obtain a white solid 3-2-13 (155 mg, yield 27%). MS Calcd.: 290.1 ​​[M+H] + MS Found: 290.4 [M+H] + .

[1107] 1 H NMR (400MHz, DMSO-d6) δ7.35 (dd, J=4.8, 1.2Hz, 1H), 7.08 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (m, 2H), 6.66 (d, J=8.8 Hz, 2H), 6.38 (d, J=6.0Hz, 1H), 6.22 (d, J=5.6Hz, 1H), 4.38 (d, J=6.0Hz, 2H), 4.09 (d, J=5.6Hz, 2H), 2.85 (s, 6H).

[1108] Example 79: Preparation of compound 3-2-14 of the present invention

[1109]

[1110] 1. Synthesis of INT-3

[1111]

[1112] INT-2 (3.3 g, 20 mmol) was dissolved in DMF (80 mL), and potassium carbonate (6.07 g, 44 mmol) was added. The mixture was stirred at 70 °C. The reaction was allowed to proceed overnight, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The product was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated at room temperature, and purified by silica gel column chromatography to give a yellow oily product INT-3 (2.5 g, 70% yield).

[1113] 2. Synthesis of INT-4

[1114]

[1115] INT-3 (2.5 g, 14 mmol) was dissolved in methanol (20 mL), Pd / C (360 mg) was added, the mixture was purged with argon and then with hydrogen, and stirred overnight under hydrogen balloon pressure. The reaction mixture was filtered through diatomaceous earth, washed with methanol, and concentrated to give a red oily product INT-4 (2.09 g, crude product).

[1116] 1 H NMR (400MHz, CDCl3) δ7.13 (d, J=7.6Hz, 1H), 6.98 (d, J=1.9Hz, 1H), 6.89 (dd, J=7.7, 1.8Hz, 1H), 3.82 (s, 2H), 2.71 (s, 6H), 2.31 (s, 3H).

[1117] 3. Synthesis of INT-5

[1118]

[1119] INT-4 (750 mg, 5 mmol) was dissolved in ethanol (10 mL), and carbon disulfide (0.9 mL, 15 mmol) and triethylamine (0.7 mL, 5 mmol) were added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 1 hour. Then, DMAP (18 mg, 0.15 mmol) and Boc2O (1.2 mL, 5 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 40:1) to give the yellow oily compound INT-5 (800 mg, 84% yield).

[1120] 4. Synthesis of 3-2-14

[1121]

[1122] INT-5 (288 mg, 1.5 mmol) and SM-4 (150 mg, 1.5 mmol) were dissolved in methyl methacrylate (M) (5 mL) and reacted overnight at room temperature. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) gave a yellow oily compound 3-2-14 (260 mg, 64% yield). HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 14 H 18 N3S + 292.0937; Found 292.0937

[1123] 1 H NMR (400MHz, CDCl3) δ7.75 (s, 2H), 7.53 (s, 1H), 7.30 (t, J=4.2Hz, 1H), 7.19 (d, J=7.9Hz, 1H ), 7.06 (dd, J=5.2, 1.1Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=74Hz, 1H), 2.71 (s, 6H), 2.32 (s, 3H).

[1124] Example 80: Preparation of compound 3-2-15 of the present invention

[1125]

[1126] 1. Synthesis of SM-27

[1127]

[1128] A solution of compound SM-26 (1 g, 5.02 mmol) in 4N hydrochloric acid / dioxane (20 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give a black oily compound SM-27 (400 mg, 80% yield).

[1129] 2. Synthesis of SM-28

[1130]

[1131] CSCl2 (463.82 mg, 4.034 mmol) was added to a THF (15 mL) solution containing compound SM-27 (400 mg, 4.034 mmol) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated to give a yellow oily compound SM-28 (380 mg, yield 67%).

[1132] 3. Synthesis of compound 110-3

[1133] Compound 110-3 was synthesized according to Example 1.

[1134] 4. Synthesis of 3-2-15

[1135]

[1136] Compounds SM-28 (601.8 mg, 4.26 mmol) and DIEA (1.1 g, 8.52 mmol) were added to a 20 mL solution of tetrahydrofuran containing compound 110-3 (500 mg, 1.728 mmol), and the mixture was stirred at 50 °C for 3 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography to give a light orange solid, compound 3-2-15 (170.8 mg, yield 13.12%). MS Calcd.: 360.0 [M+H] + MSFound: 360.0 [M+H] + .

[1137] 1 HNMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.04 (s, 1H), 7.11 (d, J = 8.0Hz, 1H), 7.01 (d, J = 4.0Hz, 1H ), 6.96 (s, 1H), 6.88-6.85 (m, 2H), 6.72 (d, J=4.0Hz, 1H), 4.69 (s, 2H), 2.61 (s, 6H), 2.27 (s, 3H).

[1138] Example 81: Preparation of compound 3-2-16 of the present invention

[1139]

[1140] 1. Synthesis of compound INT-6

[1141]

[1142] SM-19 (0.75 mL, 5.0 mmol) was measured into a 25 mL flask, and dichloromethane (14 mL) and triethylamine (0.85 mL, 6.0 mmol) were added. The mixture was cooled to 0 °C, and benzyl chloroformate (0.85 mL, 6.0 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 10 min, then cooled to room temperature and stirred overnight. After the reaction was complete, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The product was purified by silica gel column chromatography (DCM) to obtain a colorless oily product INT-6 (1.26 g, 87% yield).

[1143] 2. Synthesis of compound INT-7

[1144]

[1145] Triphenylphosphine (8.61 g, 30 mmol) was weighed into a 100 mL flask. Under argon protection, tetrahydrofuran (12 mL) and diisopropyl azodicarbonate (DIAD) (7.2 mL, 36.0 mmol) were added at 0 °C. A white solid was rapidly formed. After stirring at 0 °C for 30 min, a tetrahydrofuran solution of methanol (1.2 mL, 30.0 mmol) and SM-30 (8.61 g, 30.0 mmol) (12 mL) was added. The mixture was stirred at 0 °C for 2 h, then heated to room temperature and stirred overnight. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by silica gel column chromatography (PE / EtOAc = 10:1) to give a colorless oily product SM-31 (5.01 g, 71% yield).

[1146] SM-31 (5.01 g, 16.6 mmol) was dissolved in dichloromethane (17 mL), and trifluoroacetic acid (25.0 mL, 332.0 mmol, 20.0 equiv) was added at 0 °C, and the mixture was stirred overnight. After the reaction was complete, the mixture was quenched with ice water at 0 °C, the pH was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by silica gel column chromatography (PE / EtOAc = 5:1) to give a pale yellow oily product INT-7 (729 mg, 29% yield).

[1147] 3. Synthesis of compound INT8

[1148]

[1149] Weigh INT-6 (843 mg, 3.0 mmol) into a 100 mL flask, add hexafluoroisopropanol (30 mL), 2,3-dichloro-5,6-dicyanobenzoquinone (1.021 g, 4.5 mmol), and INT-7 (905 mg, 4.5 mmol). Under argon protection, stir at room temperature until complete. Then add sodium cyanoborohydride (900 mg, 15.0 mmol) and react at room temperature. After complete reaction, quench with water, extract with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, evaporate to dryness, and purify by silica gel column chromatography (DCM) to give a pale yellow oily product INT-8 (706 mg, 75% yield).

[1150] 1H NMR (400MHz, CDCl3) δ7.40-7.27 (m, 5H), 7.04 (d, J=7.7Hz, 1H), 6.94 (s, 1H), 6.86 (d, J=7.5Hz, 1H) , 6.00 (s, 1H), 5.06 (s, 2H), 3.42 (q, J=6.6Hz, 2H), 2.86 (t, J=6.5Hz, 2H), 2.66 (s, 6H), 2.31 (s, 3H).

[1151] 4. Synthesis of compound INT-9

[1152]

[1153] Weigh INT-8 (706 mg, 2.2 mmol) into a 10 mL test tube, add methanol (3.0 mL) and Pd / C (220 mg), purge with hydrogen, and stir at room temperature. After the reaction is complete, filter through diatomaceous earth, evaporate to dryness under reduced pressure, and purify by silica gel column chromatography to obtain a pale yellow solid INT-9 (390 mg, 99% yield).

[1154] 5. Synthesis of compound SM-28

[1155] Compound SM-28 was synthesized according to Example 74.

[1156] 6. Synthesis of compound 3-2-16

[1157]

[1158] INT-9 (178 mg, 1.0 mmol) and SM-28 (141 mg, 1.0 mmol) were dissolved in toluene (2 mL), and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, column chromatography (PE / EtOAc = 5:1) gave a yellow oily compound 3-2-16 (188 mg, 59% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N3S2H + 320.1250; Found 320.1248.

[1159] 1H NMR (400MHz, CDCl3) δ7.55 (s, 1H), 7.14 (dd, J=5.6, 1.0Hz, 1H), 7.00 (d, J=7.6Hz, 1H), 6.93-6.86 (m, 2 H), 6.82 (d, J=7.4Hz, 1H), 6.72 (s, 1H), 3.83 (s, 2H), 2.93 (t, J=6.7Hz, 2H), 2.49 (s, 6H), 2.30 (s, 3H).

[1160] Example 82: Preparation of compound 3-2-17 of the present invention

[1161]

[1162] 1. Synthesis of compound INT-13

[1163]

[1164] SM-1 was dissolved in 8.8 mL of ethanol, and CS2 (1.0 g, 13.2 mmol) and triethylamine (445 mg, 4.4 mmol) were added. The mixture was stirred at room temperature for 1 h, then transferred to 0 °C, and DMAP (16 mg, 0.13 mmol) and Boc2O (960 mg, 4.4 mmol) were added. The mixture was then allowed to react overnight at room temperature. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and column chromatography was performed to give 260 mg of INT-13, with a yield of 38%.

[1165] 2. Synthesis of compound 217-2

[1166] Compound 217-2 was synthesized according to Example 17.

[1167] 3. Synthesis of compound 3-2-17

[1168]

[1169] 217-2 (290 mg, 1.7 mmol) and INT-13 (260 mg, 1.7 mmol) were dissolved in 5.0 mL of toluene and stirred for 2 hours. The reaction was detected by TLC. After the reaction was complete, the solution was evaporated to dryness and directly passed through a column to give 390 mg of 3-2-17, with a yield of 70%. MS (ESI) m / z: [M+H] + Calcd for: 326.1; Found: 326.1.

[1170] 1H NMR (400MHz, CDCl3) δ7.55 (s, 1H), 7.24-7.12 (m, 2H), 6.97-6.81 (m, 4H), 4.94 (s, 2H), 4.30 (s, 2H), 2.29 (s, 3H).13C NMR (100MHz, CDCl3) δ180.5, 150.5, 146.1, 141.1, 138.8, 131.0, 128.3, 126.6, 125.6, 124.9, 120.0, 44.6, 41.8, 21.2.

[1171] Example 83: Preparation of compound 3-2-18 of the present invention

[1172]

[1173] 1. Synthesis of 280-3

[1174] Compound 280-3 was synthesized according to Example 13.

[1175] 2. Synthesis of INT-14

[1176]

[1177] 280-3 (500 mg, 3.3 mmol) was dissolved in tetrahydrofuran (10 mL), and carbon disulfide (2.5 g, 33 mmol) and triethylamine (506 mg, 5.0 mmol) were added. The mixture was stirred at room temperature for 1 hour, then transferred to 0 °C, and DMAP (40 mg, 0.33 mmol, 0.1 equiv.) and Boc2O (792 mg, 3.6 mmol) were added. The mixture was then allowed to react overnight at room temperature. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and column chromatography was performed to give INT-14 340 mg, with a yield of 53%.

[1178] 3. Synthesis of 3-2-18

[1179]

[1180] INT-14 (100 mg, 0.52 mmol) and SM-27 (87 mg, 0.62 mmol) were dissolved in 4 mL of dichloromethane, and triethylamine (108 μL, 0.78 mmol) was added. The mixture was stirred at room temperature until complete. After the reaction was complete, the solution was evaporated to dryness and directly passed through a column to give 3-2-1848 mg, with a yield of 31%. MS (ESI) m / z: [M+Na] + Calcd for: 292.1; Found: 282.9.

[1181] 1H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.75 (s, 1H), 7.08 (s, 1H), 7.00-6.68 (m, 5H), 2.66 (s, 6H), 2.33 (s, 3H).

[1182] Example 84: Preparation of compound 3-2-19 of the present invention

[1183]

[1184] 1. Synthesis of compound INT-10

[1185] Compound 1NT-10 was synthesized according to Example 73.

[1186] 2. Synthesis of compound 3-2-19

[1187] INT-10 (350 mg, 1.7 mmol) and SM-10 (250 mg, 1.8 mmol) were dissolved in Toluene (5 mL), and triethylamine (343 mg, 3.4 mmol) was added. The reaction was carried out at room temperature for 16 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) gave a white solid compound 3-2-19: 171 mg, 33% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N4OS + 307.1046; Found 307.1048.

[1188] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J=2.0Hz, 1H), 7.19 (d, J=7.7Hz, 1H), 6.96 (s, 1H), 6.87 (d, J=7.7Hz, 1H ), 6.21 (t, J = 1.9Hz, 1H), 5.63 (s, 1H), 4.35 (s, 2H), 2.70 (d, J = 1.2Hz, 6H), 2.33 (s, 3H), 1.69 (s, 1H).

[1189] Example 85: Preparation of compound 3-2-20 of the present invention

[1190]

[1191] 1. Synthesis of compound 110-3

[1192] Compound 110-3 was synthesized according to Example 1.

[1193] 2. Synthesis of compound 3-2-20

[1194] 110-3 (164 mg, 1.0 mmol) and SM-34 (149 mg, 1.0 mmol) were dissolved in toluene (3.0 mL) and reacted at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) gave a white solid compound 3-2-20: 220 mg, 59% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3S + 314.1686; Found 314.1684.

[1195] 1 H NMR (400MHz, CDCl3): δ7.35-7.26 (m, 3H), 7.22 (d, J=7.0Hz, 2H), 7.16 (d, J=7.6Hz, 1H), 6.92 (d, J=7.6Hz, 1H), 6.83 (s, 1H), 4.75 (s, 2H), 4.39 (s, 2H), 2.37 (s, 6H), 2.31 (s, 3H).

[1196] Example 86: Preparation of compound 3-2-21 of the present invention

[1197]

[1198] 1. Synthesis of 140-3

[1199] Compound 140-3 was synthesized according to Example 18.

[1200] 2. Synthesis of 3-2-21

[1201] 140-3 (164 mg, 1.0 mmol) and B (149 mg, 1.0 mmol) were dissolved in toluene (3.0 mL), and the reaction was carried out at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) gave a yellow oily compound 3-2-21: 203 mg, 65% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3S + 314.1686; Found 314.1689.

[1202] 1H NMR (400MHz, CDCl3): δ7.36-7.25 (m, 3H), 7.21 (d, J=6.6Hz, 2H), 7.09 (d, J=7.6Hz, 1H), 6.89 (s , 1H), 6.80 (d, J=7.6Hz, 1H), 6.07 (s, 2H), 4.63 (s, 2H), 4.52 (s, 2H), 2.65 (s, 6H), 2.29 (s, 3H).

[1203] Example 87: Preparation of compound 3-2-22 of the present invention

[1204]

[1205] 1. Synthesis of compound INT-10

[1206] Compound 1NT-10 was synthesized according to Example 73.

[1207] 2. Synthesis of compound 3-2-22

[1208] INT-10 (350 mg, 1.7 mmol) and SM-35 (250 mg, 1.8 mmol) were dissolved in toluene (5 mL) and reacted at room temperature for 16 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) gave a white solid compound 3-2-22: 171 mg, 32% yield. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 16 H 23 N4OSNa + 340.1566; Found 340.1563.

[1209] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J=2.0Hz, 1H), 7.19 (d, J=7.7Hz, 1H), 6.96 (s, 1H), 6.87 (d, J=7.7Hz, 1H ), 6.21 (t, J = 1.9Hz, 1H), 5.63 (s, 1H), 4.35 (s, 2H), 2.70 (d, J = 1.2Hz, 6H), 2.33 (s, 3H), 1.69 (s, 1H).

[1210] Example 88: Preparation of compound 3-2-23 of the present invention

[1211]

[1212] 1. Synthesis of INT-15

[1213]

[1214] Weigh SM-35 (1.89 g, 10.0 mmol), potassium carbonate (5.52 g, 40.0 mmol), and dimethylamine hydrochloride (1.64 g, 20.0 mmol) into a 100 mL flask, add DMSO (20 mL), and stir overnight at 70 °C. After the reaction is complete, cool to room temperature, dilute with an appropriate amount of ethyl acetate, extract with water to remove DMSO, dry to anhydrous sodium sulfate, evaporate to dryness, and purify by silica gel column chromatography (PE:DCM = 5:1) to obtain a light yellow oily product INT-15 (2.04 g, 95% yield).

[1215] 2. Synthesis of INT-16

[1216]

[1217] The product INT-15 (2.04 g, 9.5 mmol) was dissolved in 24 mL of anhydrous diethyl ether, and lithium aluminum hydride (722 mg, 19 mmol) was slowly added in multiple batches at 0 °C with stirring at room temperature. After the reaction was complete, 3 mL of water was added at 0 °C to quench the reaction, followed by 3 mL of 15% sodium hydroxide solution and 3 mL of water. Then, anhydrous sodium sulfate was added to dry the product. The mixture was filtered, washed with ethyl acetate, evaporated to dryness, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give a pale yellow oily product C (1.96 g, 95% yield).

[1218] 3. Synthesis of compound INT-13

[1219] Compound INT-13 was synthesized according to Example 82.

[1220] 4. Synthesis of compound 3-2-23

[1221]

[1222] Weigh INT-16 (240 mg, 1.1 mmol) into a 50 mL flask, add toluene (2.5 mL) and INT-13 (155 mg, 1.0 mmol), and stir at room temperature. After the reaction is complete, purify by silica gel column chromatography (PE / EtOAc = 5:1) to give a white solid 3-2-23: 363 mg, 97% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 19 F3N3S2 + 374.0967; Found 374.0996.

[1223] 1H NMR (400MHz, CDCl3) δ7.43-7.22 (m, 3H), 6.95-6.91 (m, 3H), 6.98-6.88 (m, 2H), 4.91 (d, J=5.1Hz, 2H), 4.49 (s, 2H), 2.53 (s, 6H).

[1224] Example 89: Preparation of compound 3-2-24 of the present invention

[1225]

[1226] 1. Synthesis of INT-17

[1227]

[1228] Morpholine (2.6 mL, 30 mmol) and potassium carbonate (4.14 g, 30 mmol) were added to a DMSO (20 mL) solution of 110-1 (1.35 g, 10 mmol). After the addition was complete, the mixture was heated to 70 °C and reacted overnight. After the reaction was complete, the solution was diluted and extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily compound INT-17, which was directly added to the next step.

[1229] 2. Synthesis of INT-18

[1230]

[1231] INT-17 (515 mg, 2.5 mmol, 1.0 equiv) was dissolved in diethyl ether (7 mL), and lithium aluminum hydride (190 mg, 5 mmol) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, 3 mL of 15% NaOH solution was added to quench the reaction, followed by the addition of 3 mL of water, and then another 3 mL of 15% NaOH solution. The mixture was filtered through diatomaceous earth and anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound INT-18 (332 mg, 64% yield).

[1232] 3. Synthesis of compound INT-13

[1233] Compound INT-13 was synthesized according to Example 82.

[1234] 4. Synthesis of 3-2-24

[1235]

[1236] INT-18 (248 mg, 1.2 mmol, 1.2 equiv.) was dissolved in toluene (2 mL), followed by the addition of SM-13 (155 mg, 1.0 mmol). The reaction was allowed to proceed at room temperature for approximately 0.5 h. After the reaction was complete, direct column chromatography (DCM) was performed to give a white solid product 3-2-24: 220 mg, 61% yield. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 18 H 23 N3NaOS2 + 384.1175; Found 384.1184.

[1237] 1 H NMR (400MHz, CDCl3) δ7.20 (dd, J=9.7, 6.4Hz, 2H), 7.09 (s, 1H), 6.95 (d, J=7.8Hz, 1H), 6.92-6.87 (m, 1H), 6.82 (d, J=5.3Hz, 2H), 4.93 (d, J=5.4Hz, 2H), 4.55-4.25 (m, 2H), 3.73 (t, J=4.4Hz, 4H), 2.76 (t, J=4.5Hz, 4H), 2.33 (s, 3H).

[1238] Example 90: Preparation of compound 3-2-25 of the present invention

[1239]

[1240] 1. Synthesis of 3-2-14

[1241] Compound 3-2-1 was synthesized according to Example 61.

[1242] 2. Synthesis of 3-2-25

[1243] 3-2-1 (280 mg, 0.84 mmol) was added to a sealed tube and dissolved in acetonitrile (15 mL), followed by ammonia (5 mL). The tube was sealed and the mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. This crude product was purified by column chromatography [dichloromethane:methanol (100:1-5:1)] and preparative liquid chromatography to obtain a grayish-white solid 3-2-25 (162.76 mg, 64%). ESI [M+H] + =304.4.

[1244] 1H NMR (400MHz, DMSO-d6) δ: 8.52 (d, J=1.4Hz, 1H), 7.99 (s, 1H), 7.81 (s, 2H), 7.33 (d, J=0.8Hz, 1H), 7.09 (d, J=7.6Hz , 1H), 7.03 (s, 1H), 6.92 (d, J=7.6Hz, 1H), 4.80 (d, J=6.4Hz, 2H), 4.34 (d, J=5.6Hz, 2H), 2.61 (s, 6H), 2.29 (s, 3H).

[1245] Example 91: Preparation of compound 3-2-26 of the present invention

[1246]

[1247] 1. Synthesis of 3-2-9

[1248] Compound 3-2-9 was synthesized according to Example 74.

[1249] 2. Synthesis of 2-7-5

[1250]

[1251] 3-2-9 (350 mg, 1.16 mmol) was dissolved in THF (20 mL) in a reaction flask. Triethylamine (351 mg, 3.40 mmol), DMAP (15 mg, 0.12 mmol), and (Boc)₂O (506 mg, 2.32 mmol) were added sequentially to the system, and the mixture was stirred overnight at 70 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was then purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] to obtain 2-7-5 (410 mg, yield 88%). MS Calcd.: 404.2 [M+H] + MS Found: 404.2 [M+H] + .

[1252] 3. Synthesis of 2-7-6

[1253]

[1254] Add 2-7-5 (403 mg, 1.0 mmol) to a reaction tube, dissolve in acetonitrile (10 mL), then add iodomethane (213 mg, 1.5 mmol), seal the tube, and stir overnight at 40 °C. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then subjected to column chromatography [petroleum ether:ethyl acetate (100:1–2:1)] to give a pale yellow solid 2-7-6 (400 mg, yield: 95%). MS Calcd.: 418.2 [M+H] +MS Found: 417.8 [M+H] + .

[1255] 3. Synthesis of 3-2-26

[1256]

[1257] Add 2-7-6 (400 mg, 0.96 mmol) to a sealed tube, dissolve in acetonitrile (10 mL), then add ammonia (5 mL), and stir overnight at 80 °C. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is then subjected to column chromatography [dichloromethane:methanol (100:1-5:1)] and SFC to give a grayish-white solid 3-2-26 (106.86 mg, yield: 39%). ESI MS Calcd.: 287.2 [M+H] + MSFound: 287.3 [M+H] + .

[1258] 1 H NMR (400MHz, CD3OD) δ: 7.21 (d, J=8.0Hz, 1H), 7.06 (s, 1H), 7.01 (s, 2H), 6.96 (d, J=7.6Hz, 1H), 4.42 (s, 2H), 4.35 (s, 2H), 2.61 (s, 6H), 2.32 (s, 3H).

[1259] Example 92: Preparation of compound 3-2-27 of the present invention

[1260]

[1261] 1. Synthesis of INT-19

[1262]

[1263] SM-36 (2.26 g, 20 mmol) was dissolved in tetrahydrofuran (12 mL), and after purging with Ar, BH3·THF (60 mL, 60 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 16 hours. The reaction was quenched with ethanol at 0 °C, and then extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 3:1) to give a colorless oily compound INT-19 (1.25 g, 63% yield).

[1264] 2. Synthesis of INT-21

[1265]

[1266] INT-19 (416 mg, 4.2 mmol, 1.0 equiv.) and INT-20 (1.3 g, 4.2 mmol) were dissolved in tetrahydrofuran (4.5 mL), followed by the addition of triphenylphosphine (1.6 g, 6.3 mmol), and then DIAD (1.2 g, 6.3 mmol) was slowly added dropwise at 0 °C. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and subjected to column chromatography (PE / EtOAc = 20:1) to give a colorless oily compound (1.11 g, 67% yield).

[1267] 3. Synthesis of compound 110-3

[1268] Compound 110-3 was synthesized according to Example 1.

[1269] 4. Synthesis of INT-22

[1270]

[1271] INT-21 (1.11 g, 2.8 mmol) and 110-3 (459 mg, 2.8 mmol) were dissolved in 1,4-1,4-dioxane (5 mL), and triethylamine (2.8 g, 28 mmol) was added. The mixture was reacted at 45 °C for 3 hours. The reaction solution was concentrated under reduced pressure and subjected to column chromatography (PE / EtOAc = 20:1) to give a colorless oily compound (925 mg, 68% yield).

[1272] 5. Synthesis of 3-2-27

[1273]

[1274] INT-22 (487 mg 1.0 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of a 1,4-dioxane hydrochloric acid solution (5 mL, 4.0 M). The mixture was reacted at room temperature for 16 hours, resulting in the precipitation of a white solid. The solid was filtered, washed with ethyl acetate, and recrystallized (MeOH / EA) to give a white solid product 3-2-27: 82 mg, 25% yield. HRMS (ESI-TOF) m / z: [M+Na] + Calcdfor C 15 H 22 N5ONa + 310.1635; Found 310.1638.

[1275] 1H NMR (400MHz, Methanol-d4) δ 8.39 (d, J=1.8Hz, 1H), 7.69 (s, 1H), 7.39 (s, 2H), 6.46 (s, 1H), 4.72 (d, J=8.4Hz, 4H), 3.34 (s, 11H), 2.45 (s, 3H).

[1276] Example 93: Preparation of compound 3-2-28 of the present invention

[1277]

[1278] 1. Synthesis of compound INT-10

[1279] Compound INT-10 was synthesized according to Example 73.

[1280] 2. Synthesis of compound 3-2-28

[1281] INT-10 (180 mg, 1.1 mmol) was dissolved in toluene (2 mL), and then SM-37 (206 mg, 1.0 mmol) was added. The reaction was allowed to proceed at room temperature for approximately 0.5 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting solid was recrystallized from PE:EtOAc to give product 3-2-28: 415 mg, 94% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 24 N3S2 + 370.1406; Found 370.1407.

[1282] 1 H NMR (400MHz, CDCl3) δ7.78 (d, J=9.2Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.37-7.27 (m, 2H), 7.16 (d, J=7.7Hz, 1 H), 7.09 (s, 1H), 6.94 (d, J=8.2Hz, 1H), 6.86 (s, 1H), 5.06 (s, 2H), 4.35 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).

[1283] Example 94: Preparation of compound 3-2-29 of the present invention

[1284]

[1285] 1. Synthesis of INT-23

[1286]

[1287] SM-37 (509 mg, 3.2 mmol) was dissolved in ether (8 mL), and lithium aluminum hydride (244 mg, 6.4 mmol) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, 3 mL of 15% NaOH solution was added to quench the reaction, followed by the addition of 3 mL of water, and then another 3 mL of 15% NaOH solution. The mixture was filtered through diatomaceous earth and anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound INT-23 (347 mg, 66% yield).

[1288] 2. Synthesis of compound INT10

[1289] Compound 1NT-10 was synthesized according to Example 73.

[1290] 3. Synthesis of 3-2-29

[1291]

[1292] INT-23 (309 mg, 1.9 mmol) was dissolved in toluene (2 mL), followed by the addition of thioisocyanate INT-10 (412 mg, 2.0 mmol). The reaction was allowed to proceed at room temperature for approximately 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting solid was recrystallized to give product 3-2-29: 248 mg, 67% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 24 N3S2 + 370.1406; Found 370.1407.

[1293] 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=8.2Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=5.4Hz, 1H), 7.31 (d, J=5.4Hz, 1H), 7.23 (d, J=6.7H z, 1H), 7.17 (d, J=7.9Hz, 1H), 6.94 (d, J=7.1Hz, 1H), 6.80 (s, 1H), 4.90 (s, 2H), 4.39 (s, 2H), 2.36 (s, 6H), 2.31 (s, 3H).

[1294] Example 95: Preparation of compound 3-2-30 of the present invention

[1295]

[1296] 1. Synthesis of 6-1-2

[1297]

[1298] 6-1-1 (2.0 g, 10 mmol) and 4N dioxane hydrochloride solution (20 mL) were added sequentially to the reaction flask, and the reaction system was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain a pale yellow solid 6-1-2 (1.0 g, yield 74%).

[1299] 2. Synthesis of 6-1-3

[1300]

[1301] SM-19 (680 mg, 5.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (3.03 g, 30 mmol) and TCDI (1.07 g, 6.0 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. 6-1-2 (675 mg, 5.0 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to give a pale yellow solid 6-1-3 (800 mg, yield 58%). MS Calcd.: 278.1 [M+H] + MS Found: 278.4 [M+H] + .

[1302] 3. Synthesis of 6-1-4

[1303]

[1304] 6-1-3 (800 mg, 2.89 mmol) was added to a reaction tube and dissolved in acetonitrile (15 mL). Iodomethane (616 mg, 4.34 mmol) was then added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) to give a pale yellow semi-solid 6-1-4 (400 mg, yield 48%). MS Calcd.: 292.1 [M+H] + MS Found: 292.4 [M+H] + .

[1305] 4. Synthesis of 3-2-20

[1306]

[1307] 6-1-4 (400 mg, 1.37 mmol) was added to a reaction tube and dissolved in acetonitrile (10 mL). Then, 25% ammonia (932 mg, 13.7 mmol) was added to the reaction system, and the mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse-phase chromatography to obtain a white solid 3-2-20 (130 mg, yield 33%). MS Calcd.: 261.1 [M+H] + MS Found: 261.4 [M+H] + .

[1308] 1 H NMR (400MHz, CD3OD) δ7.12 (d, J=8.0Hz, 1H), 6.85 (dd, J=1.6, 6.0Hz, 1H), 6.82 (dd, J=3.2, 5.6Hz, 1H), 6.78 (t, J=2.0Hz, 1H), 6.63-6.60 (m, 1H), 6.50 (dd, J=2.0, 8.4Hz, 1H), 6.43 (dd, J=1.2, 3.6Hz, 1H), 2.91 (s, 6H).

[1309] Example 96: Preparation of compound 3-2-31 of the present invention

[1310]

[1311] 1. Synthesis of 6-2-2

[1312]

[1313] SM-19 (680 mg, 5.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (3.03 g, 30 mmol) and TCDI (1.07 g, 6.0 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. Next, 6-2-1 (945 mg, 5.0 mmol) was added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to give a pale yellow solid 6-2-2 (800 mg, yield 58%). MS Calcd.: 278.1 [M+H] + MS Found: 287.4 [M+H] + .

[1314] 2. Synthesis of 6-2-3

[1315]

[1316] 6-2-2 (800 mg, 2.89 mmol) was added to a reaction tube and dissolved in acetonitrile (15 mL). Iodomethane (616 mg, 4.34 mmol) was then added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) to give a pale yellow semi-solid 6-2-3 (400 mg, yield 48%). MS Calcd.: 292.1 [M+H] + MS Found: 292.4 [M+H] + .

[1317] 3. Synthesis of 3-2-21

[1318]

[1319] 6-2-3 (400 mg, 1.37 mmol) was added to a reaction tube and dissolved in acetonitrile (10 mL). Then, 25% ammonia solution (932 mg, 13.7 mmol) was added to the reaction system, and the mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse-phase chromatography to obtain a white solid 3-2-21 (201.32 mg, yield 56%). MS Calcd.: 261.1 [M+H] + MS Found: 261.4 [M+H] + .

[1320] 1 H NMR (400MHz, CD3OD) δ7.31 (dd, J=3.2, 5.2Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 6.94-6.91 (m, 2H), 6.63 (t, J=3.6Hz, 1H), 6.54-6.50 (m, 2H), 2.91 (s, 6H).

[1321] Example 97: Preparation of compound 3-2-32 of the present invention

[1322]

[1323] SM-10 (408 mg, 3.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Triethylamine (1.52 g, 15.0 mmol) and CDI (486 mg, 3.0 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for 4 hours. SM-20 (408 mg, 3.0 mmol) was then added to the system, and the mixture was stirred at 45 °C overnight. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) and preparative liquid chromatography yielded a white solid 3-2-32 (131.88 mg, yield: 17.5%). MS Calcd.: 263.1 [M+H] + MS Found: 263.2 [M+H] + .

[1324] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 8.73 (s, 1H), 8.18 (d, J=2.0Hz, 1H), 8.09 (dd, J=8.0, 1. 6Hz, 1H), 7.23 (dd, J=7.6, 1.6Hz, 1H), 7.09-6.99 (m, 2H), 6.80 (d, J=1.6Hz, 1H), 2.62 (s, 6H).

[1325] Example 98: Preparation of compound 3-2-33 of the present invention

[1326]

[1327] 1. Synthesis of 274-2

[1328]

[1329] Compound 274-1 (5.0 g, 30.3 mmol) was added to a 500 mL reaction flask and dissolved in 150 mL of alcohol. Then, formaldehyde aqueous solution (24.0 g, 300.3 mmol), acetic acid (9.0 g, 151.5 mmol), and sodium borohydride (9.5 g, 151.5 mmol) were added sequentially, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 274-2 (5.0 g, yield: 85%). MS Calcd.: 194.1 [M+H] + MS Found: 194.4 [M+H] + .

[1330] 2. Synthesis of 274-3

[1331]

[1332] Add 274-2 (5.0 g, 25.91 mmol) and THF (120 mL) to the reaction flask, purging three times with a nitrogen balloon, and cool to 0°C in an ice bath. Slowly add lithium aluminum hydride (2.5 N in THF, 20.7 mL, 51.8 mmol), stirring overnight at room temperature. After the reaction is complete, cool the system to 0°C, slowly add water (2 mL), 15% NaOH (2 mL), and water (6 mL), stirring at room temperature for 20 minutes. Dry the mixture on anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure to obtain the crude product. Purify by normal column chromatography [dichloromethane:methanol (20:1)] to give a yellow oily substance 274-3 (4.2 g, yield: 99%). MS Calcd.: 166.1 [M+H] + MS Found: 166.3 [M+H] + .

[1333] 3. Synthesis of 274-4

[1334]

[1335] 274-3 (1.5 g, 9.09 mmol) was dissolved in concentrated HBr (20 mL), followed by the addition of thiourea (919 mg, 12.09 mmol). The mixture was purged three times with nitrogen and stirred overnight at 100°C under nitrogen atmosphere. After the reaction was complete, sodium hydroxide was added to the reaction solution until the pH reached 13, and the mixture was stirred at 100°C under nitrogen atmosphere for 0.5 hours. The reaction solution was diluted with 1 M, 30 mL of sodium hydroxide aqueous solution and extracted with ethyl acetate. The extracts were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow liquid 274-4 (0.60 g, yield: 36%). MS Calcd.: 182.1 [M+H] + MS Found: 182.3 [M+H] + .

[1336] 4. Synthesis of compound 274-5

[1337]

[1338] 274-4 (0.30 g, 1.65 mmol) was dissolved in tetrahydrofuran (15 mL), followed by the addition of sodium hydride (60%, 0.10 g, 2.48 mmol). The mixture was purged three times with nitrogen and stirred at room temperature under nitrogen atmosphere for 0.5 hours. Carbon disulfide (1.26 g, 16.55 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature under nitrogen atmosphere for another hour. The reaction mixture was evaporated to dryness to obtain crude compound 274-5 as a yellow solid.

[1339] 5. Synthesis of compound 3-2-33

[1340]

[1341] Dissolve 274-5 (0.50 g, 1.79 mmol) in tetrahydrofuran (15 mL), then add SM-50 (0.35 g, 1.97 mmol). Purge the solution three times with nitrogen and react overnight at room temperature under nitrogen atmosphere with stirring. After the reaction is complete, pour the reaction mixture into water (50 mL) and extract with ethyl acetate. Combine the extracts, wash with saturated brine, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. Analyze the crude product by silica gel column chromatography (3-2-33, 0.21 g, yield: 33%) to obtain a yellow liquid. MS Calcd.: 354.1 [M+H] + MSFound: 354.0 [M+H] + .

[1342] 1 H NMR (400MHz, DMSO-d6) δ: 7.44 (d, J=5.2, 1.2Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.12-7.11 (m, 1H), 7.01 (s, 1H), 6.97 (dd, J=6.0, 3.4Hz, 1H), 6.85 (d, J=8.0Hz, 1H), 4.94 (s, 2H), 4.68 (s, 2H), 2.05 (s, 2H), 2.60 (s, 6H), 2.26 (s, 3H).

[1343] Example 99: Preparation of compound 3-2-34 of the present invention

[1344]

[1345] 1. Synthesis of compound 274-4

[1346] Compound 274-4 was synthesized according to Example 98.

[1347] 4. Synthesis of 3-2-34

[1348]

[1349] SM-21 (189 mg, 1.66 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (503 mg, 4.98 mmol) and CDI (295 mg, 1.66 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 274-4 (300 mg, 1.66 mmol) was added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (20:1)] and prepared by reverse chromatography to give a white solid 3-2-34 (221.27 mg, yield: 42%). MS Calcd.: 321.1 [M+H] + MS Found: 321.4 [M+H] + .

[1350] 1 H NMR (400MHz, DMSO-d6) δ: 7.58 (d, J=1.6Hz, 1H), 7.55 (dd, J=2.8, 4.8Hz, 1H), 7.19 (d, J=7.6Hz, 1H), 7.12 (dd , J=1.2, 4.8Hz, 1H), 6.99 (s, 1H), 6.84 (d, J=7.6Hz, 1H), 5.25 (s, 2H), 4.17 (s, 2H), 2.59 (s, 6H), 2.26 (s, 3H).

[1351] Example 100: Preparation of compound 3-2-35 of the present invention

[1352]

[1353] 1. Synthesis of compound 274-3

[1354] Compound 274-3 was synthesized according to Example 99.

[1355] 2. Synthesis of compound 278-6-1

[1356]

[1357] Add 274-3 (500 mg, 3.03 mmol) to a reaction flask, dissolve it in tetrahydrofuran (15 mL), and slowly add sodium hydrogen (118 mg, 3.94 mmol) to the system, stirring at room temperature for half an hour. Dissolve carbon disulfide (2.3 g, 30.3 mmol) in tetrahydrofuran (10 mL) and slowly add it to the above system. After the addition is complete, react at room temperature overnight. After the reaction is complete, remove the solvent under reduced pressure to obtain crude product 278-6-1, which can be used directly in the next reaction without purification.

[1358] 3. Synthesis of compound 3-2-35

[1359]

[1360] The crude product obtained above (700 mg, 2.66 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (15 mL). SM-22 (471 mg, 2.66 mmol) was slowly added to the system. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete as detected by LCMS, the reaction solution was slowly poured into ice water (2 mL) and extracted with ethyl acetate (3 x 30 mL). The extracts were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by normal column chromatography and preparative liquid chromatography to obtain a colorless oily substance 3-2-35 (212.95 mg, yield: 24%). MS Calcd.: 338.1 [M+H] + MS Found: 338.4 [M+H] + .

[1361] 1 H NMR (400MHz, DMSO-d6) δ: 7.49 (dd, J=2.8, 4.8Hz, 1H), 7.40-7.39 (m, 1H), 7.16 (d, J=8.0Hz, 1H), 7.03 (dd, J=1 .2, 5.2Hz, 1H), 6.99 (s, 1H), 6.84 (dd, J=0.8, 7.6Hz, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 2.59 (s, 6H), 2.26 (s, 3H).

[1362] Example 101: Preparation of compound 3-2-36 of the present invention

[1363]

[1364] 1. Synthesis of compound 274-4

[1365] Compound 274-4 was synthesized according to Example 99.

[1366] 2. Synthesis of compound 3-2-26

[1367] SM-23 (200 mg, 1.54 mmol) was added to a flask and dissolved in tetrahydrofuran (10 mL). CDI (249 mg, 1.54 mmol) was then added, and the mixture was stirred at room temperature for two hours. 274-4 (278 mg, 1.54 mmol) was added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. Purification by reverse-phase chromatography yielded a pale yellow oil, 3-2-26 (155.48 mg, yield: 30%). MS Calcd.: 338.1 [M+H] +MS Found: 338.1 [M+H] + .

[1368] 1 H NMR (400MHz, CD3OD) δ7.27 (dd, J=5.2Hz, J=1.2Hz, 1H), 7.17 (d, J=7.6Hz, 1H), 7.00-6.98 (m, 2H) , 6.92-6.89 (m, 1H), 6.84 (d, J=8.0Hz, 1H), 4.47 (s, 2H), 4.35 (s, 2H), 2.63 (s, 6H), 2.28 (s, 3H).

[1369] Example 102: Preparation of compound 3-2-37 of the present invention

[1370]

[1371] 1. Synthesis of INT-24

[1372]

[1373] Add 19-1 (600 mg, 4.55 mmol) to a reaction flask, dissolve in methanol (25 mL), then add formaldehyde aqueous solution (3.69 g, 45.5 mmol), acetic acid (1.37 g, 22.75 mmol), and sodium cyanoborohydride (1.43 g, 22.75 mmol) sequentially. After addition, stir overnight at room temperature under nitrogen atmosphere. After the reaction is complete, add water (40 mL) to extinguish the reaction, extract three times with dichloromethane (40 mL), dry to anhydrous sodium sulfate, filter, remove solvent under reduced pressure, and give the residue. Purify by normal column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to give yellow oil 19-2 (560 mg, yield: 77%). MS Calcd.: 161.1 [M+H] + MS Found: 161.4 [M+H] + .

[1374] 2. Synthesis of INT-25

[1375]

[1376] Add INT-24 (560 mg, 3.50 mmol) and tetrahydrofuran (15 mL) to the reaction flask, purge three times with a nitrogen balloon, and cool to 0°C under nitrogen atmosphere. Then add lithium aluminum tetrahydrofuran (2.5 N tetrahydrofuran solution, 7.0 mmol, 2.8 mL), and stir overnight at room temperature. After the reaction is complete, cool the system to 0°C, slowly add water (0.6 mL), 15% sodium hydroxide aqueous solution (0.6 mL), and water (1.8 mL), stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter, remove solvent by vacuum distillation to obtain crude product, and purify by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain yellow oil INT-25 (300 mg, yield: 52%).

[1377] 3. Synthesis of SM-7

[1378] Compound SM-7 was synthesized according to Example 36.

[1379] 4. Synthesis of INT-25

[1380]

[1381] SM-7 (209 mg, 1.83 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (554 mg, 5.49 mmol) and CDI (297 mg, 1.83 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. INT-25 (300 mg, 1.83 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared in reverse to give a white solid 3-2-37 (170.6 mg, yield: 31%).

[1382] 1 H NMR (400MHz, DMSO-d6) δ: 8.42 (d, J=1.6Hz, 1H), 7.22 (t, J=0.8Hz, 1H), 7.02 (s, 1H), 6.99 (d, J=1.2Hz, 2H), 6.76 (t, J=5.6Hz, 1H), 6.49 (t, J=5.6Hz, 1H), 4.53 (d, J=6.0Hz, 2H), 4.26 (d, J=6.0Hz, 2H), 2.58 (s, 6H), 2.22 (s, 3H).

[1383] Example 103: Preparation of compound 3-2-38 of the present invention

[1384]

[1385] 1. Synthesis of compound 110-3

[1386] Compound 110-3 was synthesized according to Example 1.

[1387] 2. Synthesis of INT-26

[1388]

[1389] SM-39 (1.01 g, 5 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of triethylamine (1.05 mL, 7.5 mmol, 1.5 equiv). Then, 110-3 (820 mg, 5 mmol) was slowly added dropwise at -10 °C. After the addition was complete, the reaction was continued at -10 °C for 16 hours. After the reaction was complete, water was added to quench the reaction, followed by dilution with dichloromethane. The mixture was washed twice with a 20% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid compound INT-26 (1.06 g, 65% yield).

[1390] 3. Synthesis of 3-2-38

[1391]

[1392] INT-26 (2.4 g, 7.3 mmol) and SM-40 (1.2 g, 14.6 mmol) were dissolved in acetonitrile (40 mL) and reacted at 65 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was obtained by column chromatography (DCM / MeOH = 10:1). The crude product was then recrystallized from acetone to give a pale yellow solid, which was further subjected to reversed-phase column chromatography (MeCN / H2O = 50%, 30 min) to give a white solid 3-2-38: 70 mg, 3.5% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 14 H 20 N5O + 274.1662; Found 274.1667.

[1393] 1 H NMR (400MHz, CDCl3) δ7.26 (d, J=1.0Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 6.95 (s, 1H), 6. 87 (d, J=7.7Hz, 1H), 6.65 (s, 2H), 4.47 (d, J=5.6Hz, 2H), 2.69 (s, 6H), 2.31 (s, 3H).

[1394] Example 104: Preparation of compound 3-2-39 of the present invention

[1395]

[1396] 1. Synthesis of compound INT-27

[1397]

[1398] After dissolving SM-41 (812 mg, 4.0 mmol) in toluene (12 mL), solid phosgene (594 mg, 2.0 mmol) was added. After the addition was complete, the mixture was refluxed at 120 °C for 4 hours. The toluene was then evaporated to dryness. The resulting yellow oily crude product INT-27 was directly added to the next step.

[1399] 2. Synthesis of Compound 110-3

[1400] Compound 110-3 was synthesized according to Example 1.

[1401] 3. Synthesis of compound 3-2-39

[1402]

[1403] 110-3 (656 mg, 4.0 mmol) and INT-27 (436 mg, 4.0 mmol) were dissolved in dichloromethane (6.0 mL), and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) gave a yellow oily compound 3-2-39: 152 mg, 14% yield. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 14 H 19 N5oNa + 296.1482; Found 296.1481.

[1404] 1 H NMR (400MHz, CDCl3): δ8.16 (d, J=2.8Hz, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.83 ( d, J=7.6Hz, 1H), 6.48 (s, 1H), 4.61 (d, J=5.8Hz, 2H), 2.59 (s, 6H), 2.28 (s, 3H).

[1405] Example 105: Preparation of Compound 3-2-40 of the Present Invention

[1406]

[1407] 1. Synthesis of compound INT-28

[1408]

[1409] SM-42 (1.89 g, 10 mmol) was dissolved in dimethyl sulfoxide (15 mL), followed by the addition of dimethylamine hydrochloride (1.22 g, 15 mmol) and potassium carbonate (3.46 g, 25 mmol). The mixture was then heated to 70 °C and reacted overnight. After the reaction was complete, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily compound, INT-28.

[1410] 2. Synthesis of compound INT-29

[1411]

[1412] INT-28 was dissolved in diethyl ether (20 mL), and lithium aluminum hydride (0.95 g, 25 mmol) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 4 hours. After the reaction was complete, 3 mL of 15% sodium hydroxide solution was added to quench the reaction, followed by the addition of 3 mL of water, and then another 3 mL of 15% sodium hydroxide solution. The mixture was filtered through diatomaceous earth and anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound, INT-29 (1.85 g, 85% yield).

[1413] 3. Synthesis of compound INT-30

[1414]

[1415] SM-16 (4.84 g, 24 mmol) was dissolved in dichloromethane (60 mL), and triethylamine (8.4 mL, 60 mmol) was added at -10 °C. After the addition was complete, SM-39 (1.8 mL, 20 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water and extracted with dichloromethane (50 mL × 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 15:1) to give a white solid compound INT-30 (1.77 g, 34% yield).

[1416] 4. Synthesis of compound 3-2-40

[1417]

[1418] INT-29 (327 mg, 1.5 mmol) and INT-30 (393 mg, 1.5 mmol) were dissolved in acetonitrile (3.0 mL) and reacted at 65 °C for 3 hours. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) gave a yellow solid compound 3-2-40: 324 mg, 63% yield. HRMS (ESI-TOF) m / z: [M+H] +Calcd for C 16 H 19 F3N3O2 + 342.1424; Found 342.1423.

[1419] 1 H NMR (400MHz, CDCl3): δ7.49 (d, J=8.0Hz, 1H), 7.31-7.26 (m, 1H), 7.16 (s, 1H), 6.98 (d, J=8.0Hz, 1H), 6.28 (dd, J=3.0, 2.0Hz, 1H), 6.15 (d, J=3.0 Hz, 1H), 5.16 (dt, J=23.6, 5.4Hz, 2H), 4.31 (d, J=5.8Hz, 4H), 2.69 (s, 6H). 19 F NMR (376MHz, CDCl3): δ-59.8.

[1420] Example 106: Preparation of compound 3-2-41 of the present invention

[1421]

[1422] 1. Synthesis of compound INT-31

[1423]

[1424] SM-42 (250 mg, 2.5 mmol) was dissolved in dichloromethane (10 mL), and SM-43 (465 mg, 2 mmol, 1.0 equiv) was added in portions. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The solution was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give a colorless oily product INT-31 (156 mg, 1.1 mmol, 44% yield).

[1425] 2. Synthesis of Compound 110-3

[1426] Compound 110-3 was synthesized according to Example 1.

[1427] 3. Synthesis of compound 3-2-41

[1428]

[1429] INT-31 (156 mg, 1.1 mmol) and 110-3 (198 mg, 1.21 mmol) were dissolved in toluene (2 mL). After stirring at room temperature for 3 hours, a white solid precipitated. After the reaction was complete, the mixture was filtered, and the filter cake was washed with PE:EA = 10:1 to obtain a white solid product. The white solid was dissolved in chloroform and filtered through diatomaceous earth. The filtrate was concentrated to give a white solid product 3-2-41: 191 mg, 57% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 14 H 19 N4S2 + 307.1046; Found 307.1041.

[1430] 1 H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 8.50 (s, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.11 (d, J =7.7Hz, 1H), 6.97 (s, 1H), 6.86 (d, J = 7.7Hz, 1H), 4.71 (s, 2H), 2.63 (s, 6H), 2.27 (s, 3H).

[1431] Example 107: Preparation of compound 3-2-42 of the present invention

[1432]

[1433] 1. Synthesis of compound INT-10

[1434] Compound INT-10 was synthesized according to Example 73.

[1435] 2. Synthesis of compound 3-2-42

[1436] Pyrazolamide SM-44 (101 mg, 0.81 mmol) was added to 6 mL of dichloromethane, followed by INT-10 (200 mg, 0.97 mmol). The mixture was stirred at room temperature. TLC analysis was performed. After the reaction proceeded completely, the solution was evaporated to dryness and purified by column chromatography to obtain 180 mg of compound 3-2-42 (yield: 71%). MS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5S + :332.1; Found:332.1.

[1437] 1H NMR (400MHz, CDCl3) δ8.07 (d, J=90.7Hz, 2H), 7.12 (d, J=7.6Hz, 1H), 6.81 (d, J=11.8Hz, 2H), 5.76(s, 1H), 4.71(s, 2H), 4.22(s, 2H), 3.55(s, 3H), 2.39(s, 6H), 2.24(s, 3H), 2.13(s, 3H).

[1438] Example 108: Preparation of compound 3-2-43 of the present invention

[1439]

[1440] 1. Synthesis of compound 3-2-42

[1441] Compound 3-2-42 was synthesized according to Example 107.

[1442] 2. Synthesis of compound 3-2-42-A

[1443]

[1444] Iodimethane (1.10 mL, 13.58 mmol) was added to a tetrahydrofuran solution containing 3-2-42 (450 mg, 1.36 mmol), and the mixture was stirred at 40 °C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain crude 3-2-42-A, which was directly used in the next step of the reaction.

[1445] 3. Synthesis of compound 3-2-43

[1446]

[1447] Ammonia (8 mL) was added to a solution of tetrahydrofuran (5 mL) containing 3-2-42-A (480 mg, 1.39 mmol), and the mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product, which was then purified by column chromatography to give a white solid 3-2-43 (60.8 mg, yield 14%). (m / z calculated for [M+H)) + 315.1, found 315.1.

[1448] 1H NMR (400MHz, DMSO-d6) δ8.46-8.37 (m, 1H), 7.09 (d, J = 7.7Hz, 1H), 7.00 (s, 1H), 6.91 (d, J = 7.7Hz, 1H), 5.91(s, 1H), 4.36(s, 2H), 4.29(s, 2H), 3.66(s, 3H), 2.60(s, 6H), 2.28(s, 3H), 2.08(s, 3H).

[1449] Example 109: Preparation of compound 3-2-44 of the present invention

[1450]

[1451] 1. Synthesis of 140-3

[1452] Compound 140-3 was synthesized according to Example 18.

[1453] 2. Synthesis of INT-33

[1454]

[1455] Starting material 140-3 (1.0 g, 6.0 mmol) was dissolved in tetrahydrofuran (20 mL), and carbon disulfide (4.6 g, 60 mmol) and triethylamine (909 mg, 9 mmol) were added. The mixture was stirred at room temperature for 1 h, then transferred to 0 °C, and DMAP (74 mg, 0.6 mmol) and Boc₂O (1.44 g, 6.6 mmol) were added. The mixture was then brought to room temperature and reacted overnight. TLC analysis showed that after the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and column chromatography was performed to give 655 mg of the target compound INT-33, yield: 53%.

[1456] 3. Synthesis of compound 3-2-51

[1457]

[1458] Pyrazolamide SM-46 (101 mg, 0.81 mmol) was added to 6 mL of dichloromethane, followed by INT-33 (200 mg, 0.97 mmol). The mixture was stirred overnight at room temperature. TLC analysis was performed. After the reaction proceeded completely, the solution was evaporated to dryness and purified by column chromatography to obtain 185 mg of the target compound 3-2-51 (yield: 71%). MS (ESI) m / z: [M+H] + Calcd for C 16 H 24 N5S + : 318.1; Found: 318.1.

[1459] 4. Synthesis of compound 3-2-51-A

[1460]

[1461] Potassium iodide (1.28 mL, 15.75 mmol) was added to an acetonitrile (10 mL) solution containing 3-2-51 (500 mg, 1.58 mmol), and the mixture was stirred at 40 °C for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure to obtain crude 3-2-51-A, which was directly used in the next step.

[1462] 5. Synthesis of compound 3-2-44

[1463]

[1464] Ammonia (10 mL) was added to a solution of tetrahydrofuran (3 mL) containing 3-2-51-A (500 mg, 1.51 mmol), and the mixture was stirred at 80 °C for 14 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was purified by preparative chromatography to give a white solid 3-2-44 (163 mg, yield 36%). m / z calculated for [M+H] + 301.4, found 301.1.

[1465] 1 H NMR (400MHz, DMSO-d6) δ7.26 (s, 1H), 7.07-7.05 (m, 1H), 6.96 (s, 1H), 6.83-6.81 (m, 1H), 6 .11(s, 1H), 4.33-4.29(m, 2H), 4.24-4.21(m, 2H), 3.72(s, 3H), 2.60(s, 6H), 2.21(s, 3H).

[1466] Example 110: Preparation of compound 3-2-45 of the present invention

[1467]

[1468] 1. Synthesis of INT-33

[1469] Compound INT-33 was synthesized according to Example 109.

[1470] 2. Synthesis of 3-2-50

[1471]

[1472] Pyrazolamide SM-44 (80 mg, 0.64 mmol) was added to 5 mL of dichloromethane, followed by INT-33 (160 mg, 0.78 mmol). The mixture was stirred at room temperature. TLC analysis was performed. After the reaction proceeded completely, the solution was evaporated to dryness and purified by column chromatography to obtain 152 mg of the target compound 3-2-50, with a yield of 75%. HRMS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5S + :332.2; Found:332.2.

[1473] 3. Synthesis of 3-2-50-A

[1474]

[1475] Potassium iodide (1.71 mL, 21.12 mmol) was added to an acetonitrile (10 mL) solution containing 3-2-50 (700 mg, 2.11 mmol), and the mixture was stirred at 40 °C for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure to obtain crude 3-2-50-A, which was directly used in the next step.

[1476] 4. Synthesis of 3-2-45

[1477]

[1478] Ammonia (10 mL) was added to a solution of tetrahydrofuran (3 mL) containing 3-2-50-A (700 mg, 2.03 mmol), and the mixture was stirred at 80 °C for 14 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was purified by preparative chromatography to give a white solid 3-2-45 (130 mg, yield 20%). m / z calculated for [M+H] + 315.4, found 315.1.

[1479] 1 H NMR (400MHz, DMSO-d6) δ7.08-7.06 (m, 1H), 6.99 (s, 1H), 6.85-6.84 (m, 1H), 5 .86(s, 1H), 4.19(s, 4H), 3.64(s, 3H), 2.62(s, 6H), 2.23(s, 3H), 2.08(s, 3H).

[1480] Example 111: Preparation of compound 3-2-46 of the present invention

[1481]

[1482] 1. Synthesis of compound 3-2-22

[1483] Compound 3-2-22 was synthesized according to Example 87.

[1484] 2. Synthesis of compound 3-2-22-A

[1485]

[1486] Potassium iodide (1.15 mL, 14.2 mmol) was added to a tetrahydrofuran (10 mL) solution containing 3-2-22 (450 mg, 1.42 mmol), and the mixture was stirred at 40 °C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain crude 3-2-22-A, which was directly used in the next step.

[1487] 3. Synthesis of compound 3-2-46

[1488]

[1489] Ammonia (8 mL) was added to a solution of tetrahydrofuran (5 mL) containing 3-2-22-A (450 mg, 1.36 mmol), and the mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was purified by preparative chromatography to give a white solid 3-2-45 (82.7 mg, yield 21%). m / z calculated for [M+H] + 301.1, found 301.1.

[1490] 1 H NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 7.33 (d, J = 1.8Hz, 1H), 7.09 (d, J = 7.7Hz, 1H), 7.00 (s, 1H), 6.91 (d , J=7.7Hz, 1H), 6.17(d, J=1.5Hz, 1H), 4.44(s, 2H), 4.30(s, 2H), 3.76(s, 3H), 2.59(s, 6H), 2.28(s, 3H).

[1491] Example 112: Preparation of compound 3-2-47 of the present invention

[1492]

[1493] 1. Synthesis of Compound 140-3

[1494] Compound 140-3 was synthesized according to Example 18.

[1495] 2. Synthesis of compound INT-32

[1496]

[1497] Benzylamine 110-3 (1.0 g, 6.0 mmol) was dissolved in dichloromethane and placed at 0 °C. Carbonyl diimidazole SM-45 (1.46 g, 9 mmol) was added, and the mixture was stirred at 0 °C for 4 hours. The reaction mixture was evaporated to dryness and purified by column chromatography to give 990 mg of the target product INT-32, yield: 64%.

[1498] 3. Synthesis of compound 3-2-47

[1499]

[1500] Pyrazolamide SM-46 (64 mg, 0.58 mmol) was added to 3 mL of dichloromethane, followed by INT-32 (180 mg, 0.70 mmol). The mixture was stirred overnight at room temperature. TLC analysis was performed. After the reaction proceeded completely, the solution was evaporated to dryness and purified by column chromatography to obtain 154 mg of the target compound 3-2-47, yield: 82%. MS (ESI) m / z: [M+H] + Calcd for C 16 H 24 N5O: 302.1; Found: 302.0.

[1501] 1 H NMR (400MHz, CDCl3) δ7.36 (d, J=1.6Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 6.92 (s, 1H), 6.84 (d, J=7.5Hz, 1H), 6.08 (d, J=1.5H z, 1H), 4.71 (s, 1H), 4.54 (s, 1H), 4.42 (d, J=5.6Hz, 2H), 4.30 (d, J=5.6Hz, 2H), 3.81 (s, 3H), 2.67 (s, 6H), 2.29 (s, 3H).

[1502] Example 113: Preparation of compound 3-2-48 of the present invention

[1503]

[1504] 1. Synthesis of INT-32

[1505] Compound INT-32 was synthesized according to Example 112.

[1506] 2. Synthesis of 3-2-48

[1507]

[1508] Pyrazolamide INT-32 (72 mg, 0.58 mmol) was added to 3 mL of dichloromethane, followed by SM-44 (180 mg, 0.70 mmol). The mixture was stirred overnight at room temperature. TLC analysis was performed. After the reaction proceeded completely, the solution was evaporated to dryness and purified by column chromatography to obtain compound 3-2-48 150 mg, yield: 82%. MS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5O: 316.2; Found: 316.1.

[1509] 1 H NMR (400MHz, CDCl3) δ7.10 (d, J=7.4Hz, 1H), 6.92 (s, 1H), 6.84 (d, J=7.5Hz, 1H), 5.85 (s, 1H), 4.7 6(s, 1H), 4.58(s, 1H), 4.34(d, J=5.4Hz, 4H), 3.71(s, 3H), 2.67(s, 7H), 2.29(s, 3H), 2.18(s, 3H).

[1510] Example 114: Preparation of compound 3-2-49 of the present invention

[1511]

[1512] 1. Synthesis of SM-27

[1513] Compound SM-27 was synthesized according to Example 80.

[1514] 2. Synthesis of SM-27-A

[1515]

[1516] At 0°C, DIEA (1042.85 mg, 8.07 mmol) and thiophosgene (463.82 mg, 4.03 mmol) were added to a 5 mL solution of tetrahydrofuran containing SM-27 (180 mg, 2.01 mmol). The mixture was stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure to obtain a brown oily substance, SM-27-A, which was used directly in the next step.

[1517] 3. Synthesis of T7-4

[1518] Compound T7-4 was synthesized according to Example 53.

[1519] 4. Synthesis of 3-2-49

[1520]

[1521] At 0 °C, DIEA (873 mg, 6.75 mmol) and T7-4 (1045.23 mg, 5.07 mmol) were added to 10 mL of a tetrahydrofuran solution containing SM-27-A (300 mg, 1.69 mmol), and the mixture was stirred for 30 minutes. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by liquid chromatography to give a white solid 3-2-49 (196 mg, yield 33.4%). + 348.54, found 384.0.

[1522] 1 HNMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.03 (s, 1H), 7.15-7.10 (m, 1H), 7.02-6.99 (m, 1H), 6.95 (s, 1H), 6.89-6.84 (m, 2H), 6. 73-6.69(m, 1H), 4.74-4.63(m, 2H), 2.61(s, 6H), 2.56-2.52(m, 2H), 1.57-1.48(m, 2H), 1.36-1.25(m, 2H), 0.93-0.86(m, 3H).

[1523] Example 115: Preparation of Compound 3-2-50 of the Present Invention

[1524]

[1525] Compound 3-2-50 was synthesized according to Example 110.

[1526] 1 H NMR (400MHz, CDCl3) δ7.05 (d, J=7.6Hz, 1H), 6.88 (s, 2H), 6.79 (d, J=7.5Hz, 1H), 6.40 (s, 1H), 5.76(s, 1H), 4.67-4.38(m, 4H), 3.51(s, 3H), 2.61(s, 6H), 2.24(s, 3H), 2.07(s, 3H).

[1527] Example 116: Preparation of compound 3-2-51 of the present invention

[1528]

[1529] Compound 3-2-51 was synthesized according to Example 109.

[1530] 1H NMR (400MHz, CDCl3) δ7.29 (d, J=1.6Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.89 (s, 1H), 6.82 (d, J=7.5Hz, 1H) , 6.62 (s, 1H), 6.04 (s, 2H), 4.73 (d, J = 4.9Hz, 2H), 4.49 (s, 2H), 3.66 (s, 3H), 2.64 (s, 6H), 2.27 (s, 3H).

[1531] Example 117: Preparation of compound 3-2-52 of the present invention

[1532]

[1533] 1. Synthesis of compound 110-3

[1534] Compound 110-3 was synthesized according to Example 1.

[1535] 2. Synthesis of compound INT-34

[1536]

[1537] 110-3 (1.12 g, 7.1 mmol) was dissolved in dichloromethane and placed at 0 °C. SM-45 (1.72 g, 10.6 mmol) was added, and the mixture was stirred at 0 °C for 4 hours. The reaction mixture was evaporated to dryness and purified by column chromatography to obtain the target product INT-34 in 77% yield.

[1538] 3. Synthesis of compound 3-2-52

[1539]

[1540] SM-44 (100 mg, 0.8 mmol) was added to 3 mL of dichloromethane, followed by INT-34 (248 mg, 0.96 mmol). The mixture was stirred overnight at room temperature. TLC analysis was performed. After the reaction proceeded completely, the solution was evaporated to dryness and purified by column chromatography to obtain 140 mg of the target compound 3-2-52, with a yield of 56%. MS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5O: 316.2; Found: 316.2.

[1541] 1H NMR (400MHz, CDCl3) δ7.14 (d, J=8.1Hz, 1H), 6.89 (d, J=4.8Hz, 2H), 5.82 (s, 1H), 5.27 (s , 1H), 4.30 (dd, J=17.6, 4.7Hz, 4H), 3.64 (s, 3H), 2.55 (s, 6H), 2.32 (s, 3H), 2.19 (s, 3H).

[1542] Example 118: Preparation of compound 3-2-53 of the present invention

[1543]

[1544] 1. Synthesis of compound INT-35

[1545]

[1546] Under argon protection, 4-tert-butylbenzonitrile SM-47 (847 μL, 5.0 mmol) was dissolved in tetrahydrofuran (13 mL), cooled to -78 °C, and reaction solution (TMP)2Cu(CN)Li2 was slowly added. After the addition was complete, the reaction solution was placed at 0 °C for 2 hours. The reaction solution was cooled to -78 °C again, and benzylhydroxylamine (1.17 mL, 10.0 mmol) was added, followed by reaction at room temperature. After the reaction was complete, it was quenched with saturated ammonium chloride and saturated sodium thiosulfate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 3:1) to give a brown oily compound INT-35 (720 mg, 83% yield).

[1547] 2. Synthesis of compound INT-36

[1548]

[1549] INT-35 (700 mg, 4.0 mmol) was dissolved in dimethyl sulfoxide (15 mL), followed by the addition of potassium carbonate (1.66 g, 12 mmol) and methyl iodide (2.49 mL, 40.0 mmol), and the reaction was carried out at 50 °C for 48 hours. The mixture was extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give a yellow oily compound INT-36 (456 mg, 56% yield).

[1550] 3. Synthesis of compound INT-37

[1551]

[1552] INT-36 (456 mg, 2.2 mmol) was dissolved in ether (6 mL), and lithium aluminum hydride (168 mg, 4.4 mmol, 2.0 equiv) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, 3 mL of 15% NaOH solution was added to quench the reaction, followed by the addition of 3 mL of water and then 3 mL of 15% sodium hydroxide solution. The mixture was filtered through diatomaceous earth and anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound INT-37 (450 mg, 99% yield).

[1553] 4. Synthesis of compound INT-13

[1554] Compound INT-13 was synthesized according to Example 82.

[1555] 5. Synthesis of compound 3-2-53

[1556]

[1557] INT-37 (248 mg, 1.2 mmol) was dissolved in toluene (2 mL), followed by the addition of thioisocyanate INT-13 (155 mg, 1.0 mmol). After complete reaction, column chromatography (DCM / MeOH = 20:1) yielded 3-2-53: 360 mg, 99% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 19 H 28 N3S2 + 362.1719; Found 362.1721.

[1558] 1 H NMR (400MHz, CDCl3) δ7.24-7.12 (m, 3H), 7.09 (d, J=1.8Hz, 1H), 6.94 (d, J=3.4Hz, 2H), 4.95 (s, 2H), 4.35 (s, 2H), 2.50 (s, 6H), 1.30 (s, 9H).

[1559] Example 119: Preparation of compound 3-2-54 of the present invention

[1560]

[1561] 1. Synthesis of compound INT-38

[1562]

[1563] SM-48 (990 mg, 5 mmol) and cyclopropaneboronic acid (645 mg, 7.5 mmol) were dissolved in toluene (20 mL) and water (5 mL). Pd₂(dba)₃ (458 mg, 0.5 mmol) and Xant-Phos (262 mg, 0.55 mmol) were added, and the reaction was carried out at 100 °C. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give a yellow oily compound INT-38 (790 mg, 98.7% yield).

[1564] 2. Synthesis of compound INT-39

[1565]

[1566] INT-38 (790 mg, 4.93 mmol) was dissolved in DMF (15 mL), and potassium carbonate (1.0 g, 17.1 mmol) and dimethylamine hydrochloride (1.4 g, 17.1 mmol) were added. The mixture was stirred at 80 °C. After cooling to room temperature, the product was diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated at room temperature to give a yellow oily product, INT-39, which was used directly in the next step.

[1567] 3. Synthesis of compound INT-40

[1568]

[1569] INT-39 was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (182 mg, 4.8 mmol) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. The solution was first diluted with ethyl acetate (20 mL), then quenched with 15% sodium hydroxide solution (3 mL). After stirring for 15 min at room temperature, diatomaceous earth was added and stirred until homogeneous. The mixture was then filtered through diatomaceous earth. The filtrate was washed with water, dried, concentrated under reduced pressure, and subjected to column chromatography to obtain a yellow oily compound, INT-40 (330 mg, 35% yield).

[1570] 4. Synthesis of compound INT-13

[1571] Compound INT-13 was synthesized according to Example 82.

[1572] 5. Synthesis of compound 3-2-54

[1573]

[1574] INT-40 (175 mg, 0.85 mmol) and INT-13 (267 mg, 1 mmol) were dissolved in toluene (10 mL) and reacted at room temperature for 16 hours. Column chromatography gave a white solid compound 3-2-54 (76% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3S2 + 346.1406; Found 346.1409

[1575] 1 H NMR (400MHz, CDCl3) δ7.32 (dd, J=1.8, 0.9Hz, 1H), 7.14 (d, J=7.7Hz, 1H), 6.98 (d, J =1.9Hz, 1H), 6.91 (dd, J = 7.7, 1.8Hz, 1H), 6.29 (dd, J = 3.3, 1.9Hz, 1H), 6.21-6.13 (m , 1H), 4.69 (d, J=5.9Hz, 2H), 4.37 (d, J=5.7Hz, 2H), 4.31 (d, J=5.6Hz, 2H), 2.65 (s, 8 H), 1.59 (m, J=7.9, 5.0Hz, 2H), 1.38 (dt, J=14.6, 7.3Hz, 2H), 0.94 (t, J=7.3Hz, 3H).

[1576] Example 120: Preparation of compound 3-2-55 of the present invention

[1577]

[1578] 1. Synthesis of compound INT-40

[1579]

[1580] A solution of ZnCl2 (1.22 g, 9 mmol) in 10 mL of 2-methyltetrahydrofuran was cooled to -78 °C, and n-butyllithium (5.8 mL, 14.4 mmol, 2.5 min tetrahydrofuran) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 20 min. The above solution was then added to SM-49 (732 mg, 3 mmol) and Pd(t-Bu3P)2 (153 mg, 0.3 mmol) under stirring, and the reaction was carried out at room temperature for 2 h. The solution was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give the white solid compound INT-40 (417 mg, 80% yield).

[1581] 2. Synthesis of compound INT-41

[1582]

[1583] INT-40 (417 mg, 2.4 mmol) was dissolved in DMF (10 mL), and potassium carbonate (1.0 g, 7.3 mmol) and potassium iodide (0.9 mL, 14.5 mmol) were added. The mixture was stirred at 60 °C. The reaction was allowed to proceed overnight, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated at room temperature to give a yellow oily product, INT-41, which was used directly in the next step.

[1584] 3. Synthesis of compound INT-42

[1585]

[1586] INT-41 was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (182 mg, 4.8 mmol, 2 equiv.) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. The solution was diluted with ethyl acetate (20 mL), quenched with 15% sodium hydroxide solution (3 mL), and stirred at room temperature for 15 min. Diatomaceous earth was then added and stirred until homogeneous. The mixture was filtered through diatomaceous earth, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a yellow oily compound INT-42 (175 mg, 35% yield).

[1587] 4. Synthesis of compound 3-2-55

[1588]

[1589] INT-42 (175 mg, 0.85 mmol) and INT-43 (267 mg, 1 mmol) were dissolved in acetonitrile (10 mL), and DIPEA (177 μL, 1 mmol) was added. The mixture was reacted at 50 °C for 16 hours. After concentration under reduced pressure, column chromatography gave a white solid compound 3-2-55: 175 mg, 63% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 19 H 28 N3O2 + 330.2176; Found 330.2184

[1590] 1H NMR (400MHz, CDCl3) δ7.32 (dd, J=1.8, 0.9Hz, 1H), 7.14 (d, J=7.7Hz, 1H), 6.98 (d, J=1.9Hz, 1H), 6.91 (dd, J=7.7, 1.8Hz, 1H), 6.29 (dd, J=3.3, 1.9Hz, 1H), 6.18 (m, 1H ), 4.69 (d, J = 5.9Hz, 2H), 4.37 (d, J = 5.7Hz, 2H), 4.31 (d, J = 5.6Hz, 2H), 2.65 (m, 8H ), 1.59 (m, J=7.9, 5.0Hz, 2H), 1.38 (dt, J=14.6, 7.3Hz, 2H), 0.94 (t, J=7.3Hz, 3H).

[1591] Example 121: Preparation of compound 3-2-56 of the present invention (P3-5-2-2)

[1592]

[1593] 1. Synthesis of compound 274-4

[1594] Compound 274-4 was synthesized according to Example 98.

[1595] 2. Synthesis of compound 3-2-56

[1596] SM-21 (202 mg, 1.77 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (536 mg, 5.31 mmol) and TCDI (315 mg, 1.77 mmol) were then added to the system, and the mixture was stirred at room temperature for two hours. Next, 274-4 (320 mg, 1.77 mmol) was added to the system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. This crude product was purified by column chromatography and prepared in reverse order to give a white solid 3-2-56 (170.72 mg, yield: 28.7%). ESI[M+H] + =337.4[M+H] + .

[1597] 1 H NMR (400MHz, DMSO-d6) δ: 7.68 (d, J=2.0Hz, 1H), 7.59 (dd, J=2.8, 4.8Hz, 1H), 7.20 (dd, J=1.6, 5.2Hz, 1H), 7.15 ( d, J=7.6Hz, 1H), 6.99 (s, 1H), 6.81 (dd, J=0.8, 7.6Hz, 1H), 5.65 (s, 2H), 4.41 (s, 2H), 2.59 (s, 6H), 2.26 (s, 3H).

[1598] Example 122: Preparation of compound 3-2-57 of the present invention (P3-2-1-5)

[1599]

[1600] 1. Synthesis of 280-3

[1601] Compound 280-3 was synthesized according to Example 13.

[1602] 2. Synthesis of compound INT-13

[1603] Compound INT-13 was synthesized according to Example 82.

[1604] 3. Synthesis of compound 3-2-57

[1605] Compound 280-3 (483.86 mg, 3.22 mmol) and DIEA (2 mL) were added to a 10 mL solution of tetrahydrofuran containing compound INT-13 (500 mg, 3.22 mmol), and the mixture was stirred at 80 °C for 3 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified to give a light purple solid compound 3-2-57 (275 mg, yield 28%). m / z calculated for [M+H] + 306.5, found 306.1.

[1606] 1 H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.32 (s, 1H), 7.46-7.38 (m, 2H), 7.05-7.04 (m, 1H), 7.00 -6.95 (m, 1H), 6.86 (s, 1H), 6.78-6.76 (m, 1H), 4.91 (d, J=4Hz, 2H), 2.58 (s, 6H), 2.27 (s, 3H).

[1607] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[1608] Experimental Example 1: Study on the potent analgesic effect of the compound of the present invention

[1609] 1. Experimental Methods

[1610] The potent analgesic effect of the compounds of this invention was evaluated using the loss of tail withdrawal reflex (LOTWR) in rats as a criterion.

[1611] 1.1 Experimental Animals: Adult male SD rats weighing between 220 and 300 grams were selected for the experiment. The rats were housed in sawdust bedding cages at 25 ± 1 degrees Celsius, with humidity between 40% and 60%, and 12 hours of light / 12 hours of darkness. No more than 5 rats were housed per cage, and they had free access to water and food.

[1612] 1.2 Experimental Scheme:

[1613] (1) The compound of the present invention, the positive control drug remifentanil, and the negative control group (solvent) were administered in fixed volumes. The minimum effective dose at which the compound of the present invention produced a strong analgesic effect and the minimum dose at which serious adverse reactions occurred were determined by dose escalation.

[1614] (2) The duration of LOTWR for 30 seconds was used as the indicator of potent analgesia. During the experiment, the drug was administered via the tail vein of rats, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. Then, an alligator clip was placed 1 cm from the base of the rat's tail, clamping once longitudinally and once laterally, and left in place while continuously pulsating the distal end of the clip (30 times / min) to continuously generate stimulation. The clip was removed when the rat exhibited an escape response (i.e., exhibiting evasive movements, struggling, and squeaking) or when the clip remained on the tail for 30 seconds (to avoid tissue damage). If the rat exhibited an escape response, this time point was recorded as "no LOTWR," and the process was repeated after 2 minutes. When all results were "no LOTWR" after 10 minutes (5 tests), the test was stopped and recorded as "invalid."

[1615] (3) All compounds will be escalated over a dose range, starting at 1 mg / kg (the minimum dose is set at 1 μg / kg due to the high potency of remifentanil), then 5 mg / kg, 10 mg / kg, 20 mg / kg, and so on (increasing by 20 mg / kg each time after 20 mg / kg). The dose escalation will be stopped when the rats reach the lethal dose. The lowest effective dose and the lowest dose at which a serious adverse reaction occurs will be recorded throughout the process. In this study, serious adverse reactions are defined as: respiratory arrest, generalized rigidity, convulsions, opisthotonus, seizures, etc.

[1616] 1.3 Evaluation indicators: lowest effective dose; lowest dose at which serious adverse reactions occur; safe treatment index = "lowest dose at which serious adverse reactions occur" / "lowest effective dose".

[1617] 2. Experimental Results

[1618] Table 1. Efficacy and safety window of the compounds of this invention in rats (single intravenous injection)

[1619]

[1620]

[1621]

[1622]

[1623] Remark:

[1624] "-" indicates that the test was completed, and the test was ineffective or had no effect.

[1625] “A” indicates that the minimum effective dose is ≤10.00mg / kg;

[1626] "B" indicates that 10.00 mg / kg < minimum effective dose ≤ 20.00 mg / kg;

[1627] "C" indicates that 20.00 mg / kg < minimum effective dose ≤ 30.00 mg / kg;

[1628] “D” indicates that the minimum effective dose is >30.00 mg / kg.

[1629] "+" indicates that the safety treatment index is ≤2;

[1630] “++” indicates that 2 < safety treatment index ≤ 4;

[1631] "+++" indicates a safety treatment index > 4.

[1632] As shown in Table 1, both the compounds of this invention and the μ-opioid receptor agonist remifentanil can produce definite and potent systemic analgesic effects. At the same time, as shown in the table, the safety and therapeutic index of most of the compounds of this invention are significantly improved compared with the μ-opioid receptor agonist remifentanil, indicating that the compounds of this invention have better safety.

[1633] This invention provides a compound with analgesic effects. This compound exhibits excellent analgesic efficacy, good safety profile, low toxicity and side effects, and does not induce dependence. Therefore, this compound has broad application prospects in the preparation of analgesic drugs, providing a new option for the clinical preparation of drugs with analgesic effects.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula IIIa: Formula IIIa in, R3 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, halogen, hydroxyl; the alkyl group has one or two or more substituents, and each substituent is independently selected from a halogen; R6 and R7 are each independently selected from substituted or unsubstituted C1-C2 alkyl groups; the alkyl group has one or two or more substituents, and each substituent is independently selected from deuterium; m is selected from 0, 1, or 2; n is selected from 0, 1, or 2; Selected from , ; X3 is selected from O, S, NR9, and CR. 10 R 11 ; R9 is selected from hydrogen; R 10 R 11 Each is independently selected from hydrogen and nitro groups; Ring A is selected from the following groups, whether substituted or unsubstituted: , , , , , , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

2. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is represented by formula Va: Va in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, and (CH2). p CONHR 1b , halogen, hydroxyl; p is selected from 2, R 1b The alkyl group is selected from C1 to C6 alkyl groups; the alkyl group has one or two or more substituents, and each substituent is independently selected from a halogen; R6 and R7 are each independently selected from substituted or unsubstituted C1-C2 alkyl groups; the alkyl group has one or two or more substituents, and each substituent is independently selected from deuterium; m is selected from 0, 1, or 2; n is selected from 0, 1, or 2; X3 is selected from O, S, NR9, and CR. 10 R 11 ; R9 is selected from hydrogen; R 10 R 11 Each is independently selected from hydrogen and nitro groups; Ring A is selected from the following groups, whether substituted or unsubstituted: , , , , , , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

3. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula VIa: VIA in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, and (CH2). p CONHR 1b , halogen, hydroxyl; p is selected from 2, R 1b The alkyl group is selected from C1 to C6 alkyl groups; the alkyl group has one or two or more substituents, and each substituent is independently selected from a halogen; R6 and R7 are each independently selected from substituted or unsubstituted C1-C2 alkyl groups; the alkyl group has one or two or more substituents, and each substituent is independently selected from deuterium; X3 is selected from O, S, NR9, and CR. 10 R 11 ; R9 is selected from hydrogen; R 10 R 11 Each is independently selected from hydrogen and nitro groups; Ring A is selected from the following groups, whether substituted or unsubstituted: , , , , , , , , , , , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

4. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula VIb: Formula VIb in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups; the alkyl group has one or two or more substituents, and each substituent is independently selected from a halogen; R6 and R7 are each independently selected from C1~C6 alkyl groups; X3 is selected from O, S, and NR9; R9 is selected from hydrogen; Ring A is selected from the following groups, whether substituted or unsubstituted: , , , , , , The substituents of ring A are selected from C1 to C6 alkyl groups.

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula VIIa: Formula VIIa in, R3 is selected from C1~C6 alkyl groups; R6 and R7 are each independently selected from C1~C2 alkyl groups; X3 is selected from O, S, and NR9; R9 is selected from hydrogen; Ring A is selected from , , .

6. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula VIIb: Equation VIIb in, R3 is selected from hydrogen and C1-C6 alkyl groups; R6 and R7 are each independently selected from C1~C6 alkyl groups; X3 is selected from S and NR9; R9 is selected from hydrogen; Ring A is selected from , .

7. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is one of the following compounds: 。 8. Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having analgesic effects.

9. A drug, characterized in that: It is a formulation prepared by using the compound of any one of claims 1 to 7 or its pharmaceutically acceptable salt as the active ingredient, plus pharmaceutically acceptable excipients.

10. A pharmaceutical composition, characterized in that: It includes the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

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