Benzene-ring-containing compound with analgesic effect as well as preparation method and application of benzene-ring-containing compound

Abstract

The invention discloses a benzene ring-containing compound with an analgesic effect as well as a preparation method and application thereof, and relates to the field of medicinal chemistry. The compound is a compound as shown in a 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 deuterated derivative thereof. The compound is excellent in analgesic effect, good in safety in use, small in toxic and side effects and free of dependence in the use process. Therefore, the compound has a wide application prospect in preparation of analgesic drugs, and a new choice is provided for clinical preparation of drugs with analgesic effects. # imgabs0 #

Description

A benzene ring-containing compound with analgesic effect, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a benzene ring-containing compound with analgesic effect, a preparation method and use thereof. Background Art

[0002] The Global Burden of Disease Study reports that pain and pain-related conditions are the leading causes of disability and disease worldwide. The report shows that over 80% of patients undergoing surgery experience acute postoperative pain, while less than half experience adequate pain relief. Nearly 80% of patients experience moderate to severe pain severity, and 10% to 50% experience chronic pain. Therefore, there remains a significant clinical need for analgesics. In the field of pain treatment, traditional opioids remain the most effective and commonly used analgesics for treating moderate to severe pain. Opioids exert their analgesic effects by acting on opioid receptors within the G protein-coupled receptor family, primarily activating the downstream Gi / o protein pathway.

[0003] However, while opioids provide potent analgesics, they are also associated with numerous adverse reactions. These include common side effects such as respiratory depression, profound sedation, nausea and vomiting, and constipation. Long-term use can lead to tolerance, hypoalgesia, and even drug abuse and addiction, resulting in serious social harm. Opioids acting on μ receptors can produce dose-dependent respiratory depression through direct effects on the respiratory center in the human brainstem. Studies have shown that the average addiction rate for opioids ranges from 8% to 12%. Patients who are physically dependent on or addicted to opioids often abuse them to avoid withdrawal symptoms.

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

[0005] In summary, while traditional opioids used clinically are the most effective drugs for treating moderate to severe pain, their associated adverse reactions and drug dependence limit their effectiveness. Furthermore, they reduce safety and can lead to serious social problems such as drug abuse. Therefore, designing novel compounds that retain the analgesic efficacy of opioids while avoiding their severe adverse reactions to create new non-opioid analgesics has significant clinical significance and broad market prospects.

[0006] Summary of the Invention

[0007] The present invention aims to provide a benzene ring-containing compound with analgesic effect, a preparation method and use thereof.

[0008] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof:

[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 is selected from C1-C6 alkyl, 5-8 membered aryl, 5-8 membered heteroaryl, and one or more of R1 and R4 is selected from NR6R7;

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

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

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

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

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

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

[0017] X3 is selected from O, S, NR9, 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 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0020] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0021] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl;

[0022] The number of substituents of the alkyl group and the 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 of 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, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =0;

[0024] The heteroatoms in the heterocycloalkyl and heteroaryl groups are 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 represented by Formula IIa or Formula IIb:

[0029] in,

[0030] R2 and R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (CH2) p CONHR 1b , halogen, hydroxyl; p is an integer selected from 0 to 5, R 1b Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0031] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0032] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0033] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0034] X1, X2 are independently selected from O, S, NR8;

[0035] Each R8 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0036] L is selected from C=X3, substituted or unsubstituted 4- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl;

[0037] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0038] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0039] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0040] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0041] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl;

[0042] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0043] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =0;

[0044] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0045] Furthermore, the compound is represented by formula IIIa or IIIb:

[0046] in,

[0047] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0048] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0049] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0050] X1, X2 are independently selected from O, S, NR8;

[0051] Each R8 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0052] L is selected from C=X3, substituted or unsubstituted 4- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl;

[0053] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0054] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0055] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0056] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0057] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl;

[0058] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0059] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =0;

[0060] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0061] Further,

[0062] X1 and X2 are independently selected from O, S, and NH;

[0063] and / or, L is selected from

[0064] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0065] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0066] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0067] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0068] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0069] Further,

[0070] Selected from

[0071] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0072] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0073] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0074] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0075] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0076] Furthermore, the compound is represented by Formula IV:

[0077] in,

[0078] 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 is selected from C1-C6 alkyl, phenyl, and one or more of R1 and R4 is selected from NR6R7;

[0079] R2, R3, R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (CH2) p CONHR 1b , halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl;

[0080] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0081] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0082] X1, X2 are independently selected from O, S, NR8;

[0083] Each R8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0084] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0085] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0086] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0087] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0088] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl;

[0089] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0090] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy;

[0091] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0092] Furthermore, the compound is represented by formula IVa:

[0093] in,

[0094] 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 is selected from C1-C6 alkyl, phenyl, and one or more of R1 and R4 is selected from NR6R7;

[0095] R2, R3, R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl;

[0096] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0097] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0098] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl;

[0099] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0100] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy;

[0101] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0102] Furthermore, the compound is represented by formula Va or Vb:

[0103] in,

[0104] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl;

[0105] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0106] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0107] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0108] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0109] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0110] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0111] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl;

[0112] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0113] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy;

[0114] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0115] Furthermore, the compound is represented by Formula VIa or VIb:

[0116] in,

[0117] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl;

[0118] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0119] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0120] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0121] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0122] R 12 Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0123] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl;

[0124] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0125] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy;

[0126] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0127] Furthermore, the compound is represented by Formula VIIa or VIIb:

[0128] in,

[0129] R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl;

[0130] R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0131] X3 is selected from O, S, NR9, CR 10 R 11 ;

[0132] R9 is selected from hydrogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0133] R 10 、R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0134] R 12Selected from substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0135] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl;

[0136] The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0137] The number of substituents of 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, thiol, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy;

[0138] The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0139] Further,

[0140] Ring A is selected from the following substituted or unsubstituted groups:

[0141] The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy;

[0142] Preferably, the substituents of ring A are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, C1-C4 alkyl, and C1-C4 alkoxy.

[0143] Furthermore, the compound is one of the following compounds:

[0144] 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 crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, which comprises the following steps:

[0145] In a solvent, compound a, an organic base, TCDI or CDI and compound b react to obtain a compound represented by formula IV;

[0146] R1, R2, R3, R4, R5, m, n, X1, X2, and A ring are as described above; X3 is S or O;

[0147] Preferably,

[0148] The solvent is dichloromethane;

[0149] And / or, the organic base is Et3N;

[0150] And / or, the reaction temperature is 25-40° C., and the reaction time is 10-12 hours.

[0151] 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 crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, which comprises the following steps:

[0152] Step 1: Compound c reacts with CH3I in a solvent to obtain compound d;

[0153] Step 2: Compound d reacts with aqueous ammonia in a solvent to obtain a compound represented by Formula IVa;

[0154] R1, R2, R3, R4, R5, m, n, and A ring are as described above;

[0155] Preferably,

[0156] In step 1, the solvent is acetonitrile;

[0157] And / or, in step 1, the reaction temperature is 40-60° C., and the reaction time is 4-10 hours;

[0158] And / or, in step 2, the solvent is acetonitrile;

[0159] And / or, in step 2, the reaction temperature is 80-100° C., and the reaction time is 10-12 hours.

[0160] The present invention also provides the use 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 in the preparation of a drug with analgesic effect.

[0161] The present invention also provides a drug, which is a preparation prepared with 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, and pharmaceutically acceptable excipients.

[0162] 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 crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof.

[0163] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0164] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0165] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0166] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a~C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms; and "C1-C6 alkoxy" refers to an alkoxy group containing from 1 to 6 carbon atoms.

[0167] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight 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, among others.

[0168] "Halogen" is fluorine, chlorine, bromine or iodine.

[0169] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0170] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N and / or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0171] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to wait.

[0172] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N and / or S, such as but not limited to thienyl, furyl, isothiazolyl, etc.

[0173] The "5- to 8-membered aryl group" includes 5-, 6-, 7-, and 8-membered aryl groups.

[0174] The "5- to 8-membered heteroaryl group" includes 5-, 6-, 7-, and 8-membered heteroaryl groups.

[0175] The "5- to 8-membered cycloalkyl group" includes 5-, 6-, 7-, and 8-membered cycloalkyl groups.

[0176] The "5- to 8-membered heterocycloalkyl group" includes 5-, 6-, 7-, and 8-membered heterocycloalkyl groups.

[0177] The pharmaceutically acceptable salts of the present invention include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate, quaternary ammonium salt or succinate, etc.

[0178] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0179] The administration of the compound or pharmaceutical composition of the present invention includes (but is not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.

[0180] Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0181] 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 ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0182] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0183] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0184] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0185] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0186] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0187] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0188] 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 dosage when administered is a pharmaceutically safe and effective dosage.

[0189] Compared with the prior art, the compounds provided by the present invention have achieved the following beneficial effects:

[0190] The present invention provides a compound having analgesic effects. The compound has excellent analgesic effects, good safety, minimal toxic side effects, and does not cause dependence during use. Therefore, the compound has broad application prospects in the preparation of analgesic drugs and provides a new option for the clinical preparation of analgesic drugs.

[0191] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0192] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0193] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0194] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The units are given in ppm. NMR measurements were performed using a Bruker Avance III 400 NMR 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).

[0195] LCMS analysis (Agilent LCMS 1200-6120) (ESI), chromatographic column: Waters Xbridge Prep C 18OBD 10 μm, 19 x 250 mm. Column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] over 1.6 minutes to 5% [water + 10 mM ammonium bicarbonate] and 95% [CH3CN], held for 1.4 minutes, then to 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] over 0.05 minutes, held for 0.7 minutes.

[0196] (1) Medicinal materials and reagents

[0197] The manufacturer of the thin layer chromatography silica gel plate used in thin layer chromatography (TLC) is Qingdao Pu Ke Separation Materials Co., Ltd., with a specification of 50*200mm and a thickness of 0.2-0.25mm.

[0198] Column chromatography silica gel: 200-300 mesh silica gel from Shandong Weihai Rushan Sun Desiccant Co., Ltd.

[0199] (2) Main instruments

[0200] Electronic balance, FA2004, Shanghai Liangping Instrument Co., Ltd.;

[0201] Temperature-controlled and pressure-regulated magnetic stirrer, TY98-1, Shanghai Silu Instrument Co., Ltd.;

[0202] Three-purpose UV analyzer, model ZF-2, Shanghai Anting Scientific Instrument Factory;

[0203] Rotary evaporator, R201, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0204] Liftable water bath, R201D, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0205] Circulating water vacuum pump (desktop), SHB-Ⅲ, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0206] Circulating water vacuum pump (mobile), SHB-B95, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0207] Low-temperature circulation pump, DLSB-5 / 20, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0208] Rotary vane vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory.

[0209] Example 1. Preparation of Compound 1-1-1 of the Present Invention

[0210] Synthesis of 1.110-2

[0211] To a 250 mL sealed tube, 110-1 (5.0 g, 37 mmol) and a solution of dimethylamine in tetrahydrofuran (2N, 100 mL) were added and stirred at 70°C for three days. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by normal phase column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford 110-2 as a yellow oil (3.2 g, yield: 89.9%). MS Calcd.: 161.1 [M+H] + ;MS Found:161.4[M+H] + .

[0212] Synthesis of 2.110-3

[0213] To a reaction flask, 110-2 (3.2 g, 20 mmol) and diethyl ether (50 mL) were added. The atmosphere was replaced three times with a nitrogen balloon and cooled to 0°C under a nitrogen atmosphere. Lithium aluminum hydride (2.5N in THF, 16 mL) was then added and stirred at room temperature overnight. After the reaction was complete, water (3 mL), 15% sodium hydroxide (3 mL), and water (6 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a normal phase column [dichloromethane:methanol (100:1-20:1)] afforded 110-3 as a yellow oil (2.0 g, 61% yield).

[0214] 3. Synthesis of Compound 1-1-1

[0215] 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 stirred at room temperature for two hours. SM-1 (452 ​​mg, 4.0 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse phase chromatography to obtain 1-1-1 (689.35 mg, 57%) as a white solid. MS Calcd.: 304.1 [M+H] + ;MS Found:304.4[M+H] + .

[0216] 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).

[0217] Example 2. Preparation of Compound 1-1-2 of the Present Invention

[0218] 1. Preparation of Compound 110-3

[0219] Compound 110-3 was prepared according to the method described in Example 1.

[0220] 2. Preparation of compound 1-1-2

[0221] To a solution of 2-(aminomethyl)-N,N,5-trimethylaniline (110-3, 492 mg, 3 mmol) in 20 mL of dichloromethane was added TCDI (1.07 g, 3.6 mmol) and triethylamine (1.25 g, 12 mmol). After stirring at room temperature for 2 hours, thiophene-3-methylamine (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 phase to afford 1-(2-(dimethylamino)-4-methylbenzyl)-3-(thiophen-3-ylmethyl)thiourea (Compound 1-1-2, 500 mg, 52% yield) as a yellow solid. MS Calcd.: 320.1 [M+H] + ;MS Found:320.2[M+H] + .

[0222] 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).

[0223] Example 3. Preparation of Compound 1-1-3 of the Present Invention

[0224] 1. Preparation of compound 1-1-2

[0225] Compound 1-1-2 was prepared according to the method described in Example 2.

[0226] 2. Synthesis of AL-37-23-188-A

[0227] To a solution of 1-1-2 (319 mg, 1 mmol) in 20 mL of acetonitrile was added iodomethane (800 mg, 6 mmol) and stirred at 40°C for 4 hours. 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 afford a mixture of methyl (Z)-N-(2-(dimethylamino)-4-methylbenzyl)-N'-(thiophen-3-ylmethyl)aminothiocarbamate and methyl (Z)-N'-(2-(dimethylamino)-4-methylbenzyl)-N-(thiophen-3-ylmethyl)aminothiocarbamate as a pale yellow oil (AL-37-23-188-A 200 mg, 60% yield).

[0228] 3. Synthesis of compound 1-1-3

[0229] To a mixture of methyl (Z)-N-(2-(dimethylamino)-4-methylbenzyl)-N'-(thiophen-3-ylmethyl)aminothiocarbamate and methyl (Z)-N'-(2-(dimethylamino)-4-methylbenzyl)-N-(thiophen-3-ylmethyl)aminothiocarbamate (AL37-23-188-A, 200 mg, 0.6 mmol) in 10 mL of acetonitrile was added aqueous ammonia (600 mg, 6.0 mmol) and stirred at 80°C overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid phase to afford 1-(2-(dimethylamino)-4-methylbenzyl)-3-(thiophen-3-ylmethyl)guanidine (Compound 1-1-3, 30 mg, 17% yield) as a white solid. MS Calcd.: 303.2 [M+H] + ;MS Found:303.2[M+H] + .

[0230] 1 H 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).

[0231] Example 4. Preparation of Compound 1-1-4 of the Present Invention

[0232] 1. Preparation of Compound 110-3

[0233] Compound 110-3 was prepared according to the method described in Example 1.

[0234] 2. Synthesis of 189-1

[0235] To a solution of 2-(aminomethyl)-N,N,5-trimethylaniline (110-3, 492 mg, 3 mmol) and SM-2 (714 mg, 3 mmol) in 20 mL of isopropanol was added triethylamine (606 mg, 6 mmol) and stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated to yield a crude residue, which was purified by column chromatography (DCM / MeOH = 30 / 1) to afford (Z)-N'-cyano-N-(2-(dimethylamino)-4-methylbenzyl)carbamic acid phenyl ester (189-1, 500 mg, 54% yield) as a pale yellow oil.

[0236] 3. Synthesis of compound 1-1-4

[0237] To a 10 mL isopropanol solution containing 189-1 (308 mg, 1 mmol) and thiophen-3-ylmethylamine (SM-1, 113 mg, 1 mmol) was added triethylamine (303 mg, 3 mmol), and the mixture was stirred at 80°C overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid phase to afford (Z)-N'-cyano-N-(2-(dimethylamino)-4-methylbenzyl)carbamic acid phenyl ester (compound 1-1-4, 104.74 mg, 32% yield) as a white solid.

[0238] 1 H 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).

[0239] Example 5. Preparation of Compound 1-1-6 of the Present Invention

[0240] 1. Preparation of Compound 110-3

[0241] Compound 110-3 was prepared according to the method described in Example 1.

[0242] 2. Synthesis of compound 1-1-6

[0243] To a dichloromethane / acetonitrile mixture (10 / 20 mL) containing thiophen-3-ylmethanol (SM-3, 342 mg, 3 mmol) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (922 mg, 3.6 mmol) under nitrogen at 0°C. 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 at room temperature overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by column chromatography and preparative liquid phase to afford 1-1-6 as an off-white solid (98.25 mg, 11% yield).

[0244] 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).

[0245] Example 6. Preparation of Compound 1-1-7 of the Present Invention

[0246] To a DMF solution (10 mL) containing thiophen-3-ylmethylamine (SM-1, 226 mg, 2 mmol) was added CDI (389 mg, 2.4 mmol) and triethylamine (707 mg, 7.0 mmol). After stirring at room temperature for 2 hours, (2-(dimethylamino)-4-methylphenyl)methanol (274-4, 330 mg, 2 mmol) was added and 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 obtain 2-(dimethylamino)-4-methylbenzyl(thiophen-3-ylmethyl)carbamate (Compound 1-1-7, 57.98 mg, 10% yield) as an off-white solid. MS Calcd.: 305.2 [M+H] + ;MS Found:305.2[M+H] +

[0247] 1H 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).

[0248] Example 7. Preparation of Compound 1-1-8 of the Present Invention

[0249] 1. Preparation of Compound 110-3

[0250] Compound 110-3 was prepared according to the method described in Example 1.

[0251] 2. Synthesis of Compound 191-1

[0252] To a solution of 2-(aminomethyl)-N,N,5-trimethylaniline (110-3,492 mg, 3 mmol) and 1,1-bis(methylthio)-2-nitrosoethylene (495 mg, 3 mmol) in 20 mL of ethanol was added triethylamine (606 mg, 6 mmol), and the mixture was stirred at 80°C overnight. 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 afford N,N,5-trimethyl-2-(((1-(methylthio)-2-nitrosovinyl)amino)methyl)aniline (191-1,500 mg, 60% yield) as a pale yellow oil.

[0253] 3. Synthesis of 1-1-8

[0254] To a 10 mL ethanol solution containing 191-1 (281 mg, 1 mmol) and thiophen-3-ylmethylamine (113 mg, 1 mmol) was added triethylamine (303 mg, 3 mmol) and stirred at 80°C overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid phase to afford 1-1-8 as a white solid (87.86 mg, 25% yield).

[0255] 1H 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).

[0256] Example 8 Preparation of Compound 1-1-10 of the Present Invention

[0257] 1. Synthesis of 193-1

[0258] SM-1 (200 mg, 1.77 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Compound 193-0 (251 mg, 1.77 mmol) was then added and stirred at room temperature under nitrogen overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by a forward column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford compound 193-1 as a yellow oil (300 mg, yield: 76%). MS Calcd.: 224.1 [M+H] + ;MS Found:224.3[M+H] + .

[0259] 2. Preparation of Compound 110-3

[0260] Compound 110-3 was prepared according to the method described in Example 1.

[0261] 3. Synthesis of 1-1-10

[0262] 193-1 (200 mg, 0.90 mmol) was added to a reaction flask and dissolved in dichloromethane (5 mL). 110-3 (147 mg, 0.90 mmol) was then added and stirred at room temperature overnight under a nitrogen atmosphere. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by normal phase column chromatography [dichloromethane:methanol (100:1-20:1)] to afford 1-1-10 as a yellow oil (110.74 mg, yield: 35%). MS Calcd.: 356.1 [M+H] + ;MS Found:356.4[M+H] + .

[0263] 1 H NMR (400 MHz, 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).

[0264] Example 9. Preparation of Compound 1-1-1-A of the Present Invention

[0265] 1. Preparation of Compound 110-3

[0266] Compound 110-3 was prepared according to the method described in Example 1.

[0267] 2. Preparation of 1-1-1-A

[0268] To a solution of 110-3 (164 mg, 1.0 mmol) in 10 mL of dichloromethane were added CDI (243 mg, 1.5 mmol) and triethylamine (500 mg, 5.0 mmol). The mixture was stirred at room temperature for 2 hours, followed by the addition of furan-3-ylmethylamine (100 mg, 1.0 mmol), and the mixture was stirred at room temperature overnight. After the reaction was complete, the combined organic phases were concentrated under reduced pressure to afford the crude product, which was then purified by preparative liquid chromatography to afford 1-1-1-A (139.88 mg, 49% yield) as a white solid.

[0269] 1 H NMR (400 MHz, DMSO-d6) δ: 7.59 (s, 1H), 7.50 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.40 (s, 1H), 6.22 (t, J = 6.8 Hz, 1H), 4.22 (t, J = 6.0 Hz, 2H), 4.04 (t, J = 5.6 Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H). Example 10. Preparation of Compound 1-1-27 of the Present Invention

[0270] 1. Preparation of Compound 110-3

[0271] Compound 110-3 was prepared according to the method described in Example 1.

[0272] 2. Preparation of compound 1-1-27

[0273] 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 stirred for 2 hours. 2-Thienylmethylamine (226 mg, 2.0 mmol) was then added to the mixture. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a 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, 33% yield).

[0274] 1 H 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).

[0275] Example 11. Preparation of Compound 1-1-64 of the Present Invention

[0276] 1. Synthesis of 60-2

[0277] To a solution of 2-(4-bromo-2-nitrophenyl)acetic acid (60-1, 2.59 g, 10 mmol) in 50 mL of methanol was added 5 mL of concentrated sulfuric acid and heated under reflux for 20 hours. After the reaction was complete, 100 mL of water was slowly added to the reaction system to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The crude product was purified by column chromatography (PE / EA = 5 / 1) to afford methyl 2-(4-bromo-2-nitrophenyl)acetate (60-2, 2.3 g, 84%) as a pale yellow solid.

[0278] 2. Synthesis of 60-3

[0279] 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) was added Pd(dppf)Cl2·DCM (680 mg, 0.84 mmol). The mixture was stirred at 100°C for 6 hours. After the reaction was complete, 50 mL of 1N aqueous hydrochloric acid was slowly added to the reaction system to quench the reaction. The mixture was then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The crude product was purified by column chromatography (PE / EA = 5 / 1) to afford 60-3 (2.3 g, 84%) as a pale yellow oil.

[0280] 3. Synthesis of 60-4

[0281] To a solution of 60-3 (1.4 g, 6.7 mmol) in 100 mL of ethanol was added 10% Pd / C (280 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. After the reaction was complete, the reaction mixture was filtered and concentrated to afford 60-4 (1.1 g, 92%) as a pale yellow oil.

[0282] 4. Synthesis of 60-5

[0283] To a solution of 60-4 (1.1 g, 6.15 mmol), 30% formaldehyde (aqueous solution) (2.77 g, 36.9 mmol), and 5 mL of acetic acid in 30 mL of methanol was added sodium cyanoborohydride (775 mg, 12.3 mmol) and stirred at room temperature for 4 hours. After the reaction was complete, 50 mL of water was slowly added to the reaction system to quench it, followed by extraction three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The crude product was purified by column chromatography (PE / EA = 1 / 1) to afford 2-(2-(dimethylamino)-4-methylphenyl)acetate (60-5, 700 mg, 55%) as a colorless oil.

[0284] 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).

[0285] 5. Synthesis of 60-11

[0286] To a methanol / water mixture (12 / 3 mL) containing 60-5 (700 mg, 3.38 mmol) was added lithium hydroxide (425 mg, 10.14 mmol), and the mixture was stirred at 100°C for 6 hours. After the reaction was complete, 4N aqueous citric acid was slowly added to the reaction system to quench the reaction, and the mixture was concentrated to obtain a residue. The crude product was purified by reverse phase chromatography (H2O / MeCN = 3 / 1) to obtain 2-(2-(dimethylamino)-4-methylphenyl)acetic acid (60-11, 600 mg, 92%) as a colorless oil.

[0287] 6. Synthesis of 60-10

[0288] To a solution of 60-11 (600 mg, 3.11 mmol), ammonium chloride (830 mg, 15.55 mmol), and DIPEA (1.7 g, 12.44 mmol) in 30 mL of DMF were added EDCI (886 mg, 4.67 mmol) and HOBT (610 mg, 4.67 mmol), and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction system was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to afford 2-(2-(dimethylamino)-4-methylphenyl)acetamide (60-10, 450 mg, 75%) as a white solid.

[0289] 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).

[0290] 7. Synthesis of 60-9

[0291] To a solution of 60-10 (192 mg, 1.0 mmol) in 10 mL of tetrahydrofuran was added BH3-THF (1.0 N in THF, 4.0 mL) at 0°C under nitrogen, and the mixture was stirred at 70°C for 16 hours. After the reaction was complete, 2 mL of 1N hydrochloric acid was slowly added to the reaction system for quenching. After concentration, 2-(2-aminoethyl)-N,N,5-trimethylaniline hydrochloride (60-9, 250 mg, 100%) was obtained as an off-white solid.

[0292] 8. Synthesis of compound 1-1-64

[0293] To a solution of 60-9 (108 mg, 0.5 mmol) in 20 mL of DCM were added triethylamine (30 mg, 3.0 mmol), CDI (124.5 mg, 0.75 mmol), and diethyl ether (204 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 hours, followed by the addition of thiophen-3-ylmethylamine (57.5 mg, 0.5 mmol), and stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under vacuum to afford a crude residue, which was purified by preparative liquid chromatography to afford 1-(2-(dimethylamino)-4-methylphenethyl)-3-(thiophen-3-ylmethyl)urea (1-1-64, 43.60 mg, 27%) as a white solid.

[0294] 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).

[0295] Example 12. Preparation of Compound 1-1-66 of the Present Invention

[0296] To a solution of 2-(thiophen-3-yl)ethan-1-amine (254 mg, 2.0 mmol) in 20 mL of dichloromethane was added CDI (486 mg, 3.0 mmol) and triethylamine (1.0 g, 10.0 mmol). The mixture was stirred at room temperature for 2 hours, followed by the addition of 2-(aminomethyl)-N,N,5-trimethylaniline (110-3, 328 mg, 2.0 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the product was concentrated under vacuum to afford a crude residue, which was purified by preparative liquid chromatography to afford 1-(2-(dimethylamino)-4-methylbenzyl)-3-(2-(thiophen-3-yl)ethyl)urea (1-1-66, 138.87 mg, 22% yield) as a white solid.

[0297] 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).

[0298] Example 13. Preparation of Compound 1-1-63 of the Present Invention

[0299] 1. Synthesis of 280-2

[0300] To a 250 mL sealed tube, 280-1 (2.2 g, 14.19 mmol) and a solution of dimethylamine in tetrahydrofuran (2N, 60 mL) were added and heated under reflux for three days. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by forward column chromatography [petroleum ether:ethyl acetate (100:1-10:1)] to afford 280-2 as a yellow oil (3.2 g, yield: 89.9%). MS Calcd.: 181.1 [M+H] + ;MS Found:181.4[M+H] + .

[0301] 2. Synthesis of 280-3

[0302] To a reaction flask, 280-2 (1.9 g, 10.56 mmol) was added and dissolved in methanol (110 mL). Pd / C (380 mg) was then added and the mixture was replaced with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. After completion of the reaction, the mixture was filtered and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (100:1-20:1)) to afford 280-3 as a yellow oil (1.26 g, 80% yield). MS Calcd.: 161.1 [M+H] + ;MS Found:161.4[M+H] + .

[0303] 3. Synthesis of 1-1-63

[0304] Compound 280-3 (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 mixture and stirred at room temperature for two hours. SM-4 (122 mg, 1.08 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase purification to afford 1-1-63 (108.79 mg, 34%) as a white solid. MS Calcd.: 276.1 [M+H] + ;MS Found:276.4[M+H] + . .

[0305] 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).

[0306] Example 14. Preparation of Compound 1-1-107 of the Present Invention

[0307] 1. Synthesis of 188-2-1

[0308] 280-3 (550 mg, 3.67 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (1.48 g, 14.67 mmol) and TCDI (892 mg, 5.51 mmol) were added to the mixture and stirred at room temperature for two hours. SM-4 (363 mg, 3.67 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase purification to afford 188-2-1 (710 mg, 66.5%) as a white solid. MS Calcd.: 292.1 [M+H] + ;MS Found:292.1[M+H] + .

[0309] 2. Synthesis of 188-2-2

[0310] 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. The mixture was sealed and stirred at 40°C for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] afforded 188-2-2 (450 mg, 78%) as an off-white solid. MS Calcd.: 306.1 [M+H] + ;MS Found:306.2[M+H] + .

[0311] 3. Synthesis of 1-1-107

[0312] 188-2-2 (430 mg, 1.41 mmol) was added to a sealed tube and dissolved in acetonitrile (15 mL). Ammonia (3 mL) was then added, and the tube was sealed and stirred at 80°C for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] and preparative liquid chromatography afforded an off-white solid, 1-1-107 (112.90 mg, 39.5%). MS Calcd.: 275.1 [M+H] + ;MS Found:275.4[M+H] + .

[0313] 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).

[0314] Example 15. Preparation of Compound 1-1-188 of the Present Invention

[0315] 1. Synthesis of 181-2

[0316] To a 250 mL sealed tube, 181-1 (3.0 g, 19.87 mmol) and a solution of dimethylamine in tetrahydrofuran (2N, 100 mL) were added and stirred at 70°C for three days. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by a forward column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford 181-2 as a yellow oil (3.1 g, yield: 88.5%). MS Calcd.: 177.1 [M+H]+ ;MS Found:177.4[M+H] + .

[0317] 2. Synthesis of 181-3

[0318] To a reaction flask, 181-2 (2.0 g, 20 mmol) and Et2O (50 mL) were added. The atmosphere was replaced with a nitrogen balloon three times and cooled to 0°C under a nitrogen atmosphere. Lithium aluminum hydride (2.5N in THF, 16 mL) was then added and the mixture was stirred at room temperature overnight. After the reaction was complete, water (2 mL), 15% sodium hydroxide (2 mL), and water (6 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography [dichloromethane:methanol (100:1-20:1)] afforded 181-3 as a yellow oil (1.6 g, yield: 78%). MS Calcd.: 181.1 [M+H] + ;MS Found:181.2[M+H] + .

[0319] 3. Synthesis of 181-4

[0320] Compound 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 mixture and stirred at room temperature for two hours. SM-1 (265 mg, 2.32 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase purification to afford compound 181-4 (420 mg, yield: 56.5%) as a white solid. MS Calcd.: 320.1 [M+H] + ;MS Found:320.2[M+H] + .

[0321] 1H 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).

[0322] 4. Synthesis of 1-1-188

[0323] To a reaction flask, 181-4 (220 mg, 0.69 mmol) was added and dissolved in tetrahydrofuran (10 mL). The mixture was replaced with a nitrogen balloon three times and cooled to 0°C under a nitrogen atmosphere. Boron tribromide (2.07 mmol, 2.0 N in THF, 1.04 mL) was added and stirred at room temperature for three hours. After completion of the reaction, the mixture was slowly poured into water (10 mL) and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane (20 mL). The organic phase was washed once with saturated brine, separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. This was then purified by forward column chromatography [dichloromethane:methanol (100:1-20:1)] to afford 1-1-188 as a yellow oil (51.37 mg, yield: 24.7%). MS Calcd.: 306.1 [M+H] + ;MS Found:306.2[M+H] + .

[0324] 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).

[0325] Example 16. Preparation of Compound 1-1-177 of the Present Invention

[0326] 1. Synthesis of 180-2

[0327] To a 100 mL reaction flask, 180-1 (1.0 g, 7.41 mmol) was added and dissolved in DMF (10 mL). NaH (1.0 g, 7.41 mmol) was added at 0°C and allowed to react at room temperature for 2 h. CHCl (1.0 g, 7.41 mmol) was then added and stirred at room temperature overnight. After completion, the reaction solution was slowly poured into ice water and extracted three times with dichloromethane (40 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography (petroleum ether:ethyl acetate (100:1-10:1)) afforded 180-2 as a brownish-yellow oil (1.2 g, yield: 81%). MS Calcd.: 165.1 [M+H] + ;MS Found:165.4[M+H] + .

[0328] 2. Synthesis of 180-3

[0329] To a reaction flask, 180-2 (602 mg, 3.01 mmol) and diethyl ether (20 mL) were added. The atmosphere was replaced three times with a nitrogen balloon and cooled to 0°C under a nitrogen atmosphere. Lithium aluminum hydride (2.5N in THF, 2.4 mL) was then added and stirred at room temperature overnight. After the reaction was complete, water (1 mL), 15% NaOH (3 mL), and water (3 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography [dichloromethane:methanol (100:1-20:1)] afforded 180-3 as a yellow oil (2.0 g, 61% yield).

[0330] 3. Synthesis of 1-1-177

[0331] 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 stirred at room temperature for two hours. SM-1 (122 mg, 1.08 mmol) was then added to the system and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase preparation to obtain 1-1-177 (125.06 mg, 34%) as a white solid. MS Calcd.: 344.2 [M+H] + ;MS Found:344.4[M+H] + .

[0332] 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).

[0333] Example 17. Preparation of Compound 1-1-191 of the Present Invention

[0334] 1. Synthesis of 217-1

[0335] To a solution of 2-amino-4-methylbenzonitrile (217-3, 660 mg, 5.0 mmol) in 50 mL of tetrahydrofuran was added 60% sodium hydride (440 mg, 11.0 mmol). After stirring at room temperature for half an hour, deuterated iodomethane (1.45 g, 10.0 mmol) was added and stirred at room temperature overnight. After the reaction was complete, water was slowly added to the reaction system to quench the reaction, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The crude product was purified by column chromatography (DCM / MeOH = 3 / 1) to afford 2-(bis(methyl-d3)amino)-4-methylbenzonitrile (217-1, 680 mg, 82% yield) as a yellow oil.

[0336] 2. Synthesis of 217-2

[0337] To a solution of 217-1 (332 mg, 2.0 mmol) in 20 mL of diethyl ether was added lithium aluminum hydride (2.5 N in THF, 1.6 mL) at 0°C under nitrogen, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, 0.1 mL of water, 0.1 mL of 15% sodium hydroxide solution, and 0.3 mL of water were slowly added to the reaction system to quench the mixture. The mixture was filtered and concentrated to obtain a residue. The crude product was purified by flash column chromatography on silica gel (DCM:MeOH = 20:1) to afford 2-(aminomethyl)-5-methyl-N,N-dimethyl(d3)aniline (217-2, 250 mg, 74% yield) as a yellow oil.

[0338] 3. Synthesis of 1-1-191

[0339] To a solution of 217-2 (340 mg, 2.0 mmol) in 20 mL of dichloromethane were added CDI (486 mg, 3.0 mmol) and triethylamine (1.0 g, 10.0 mmol). After stirring at room temperature for 2 hours, thiophen-3-ylmethylamine (226 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated to afford a crude residue, which was purified by preparative liquid phase to afford 1-((1H-imidazol-2-yl)methyl)-3-(2-(dimethyl(d3)amino)-4-methylbenzyl)urea (1-1-191, 187 mg, 30% yield) as a white solid.

[0340] 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).

[0341] Example 18. Preparation of Compound 1-2-1 of the Present Invention

[0342] 1. Synthesis of 140-2

[0343] To a reaction flask, 140-1 (3.0 g, 22.73 mmol), aqueous formaldehyde (8.5 g, 113.65 mmol), glacial acetic acid (5 mL), and methanol (45 mL) were added. Under nitrogen protection, sodium cyanoborohydride (7.2 g, 113.65 mmol) was added and the atmosphere was replaced with a nitrogen balloon three times. The reaction was stirred at room temperature under nitrogen overnight. After completion of the reaction, the mixture was poured into water (100 mL) and extracted three times with dichloromethane (100 mL). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a reverse phase column gave 140-2 as a yellow oil (3.2 g, yield: 90%). MS Calcd.: 161.1 [M+H] + ;MS Found:161.4[M+H] + .

[0344] 2. Synthesis of 140-3

[0345] To a reaction flask, 140-2 (600 mg, 3.75 mmol) and Et2O (20 mL) were added. The atmosphere was replaced with a nitrogen balloon three times and cooled to 0°C under a nitrogen atmosphere. Lithium aluminum hydride (4.8 g, 22.0 mmol) was then added and stirred at room temperature overnight. After the reaction was complete, water (1 mL), 15% sodium hydroxide solution (1 mL), and water (3 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography afforded 140-3 as a yellow oil (420 mg, 68%). MS Calcd.: 165.1 [M+H] + ;MS Found:165.4[M+H] + .

[0346] 3. Synthesis of compound 1-2-1

[0347] 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 added to the system and stirred at room temperature for two hours. 140-3 (220 mg, 1.34 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse synthesis afforded compound 1-2-1 (83.75 mg, 21%) as a white solid. MS Calcd.: 304.1 [M+H] + ;MS Found:304.2[M+H] + .

[0348] 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).

[0349] Example 19. Preparation of Compound 1-2-2 of the Present Invention

[0350] 1. Synthesis of 140-3

[0351] Compound 140-3 was synthesized according to Example 18.

[0352] 2. Synthesis of compound 1-2-2

[0353] To a solution of 5-(aminomethyl)-N,N,2-trimethylaniline (140-3, 492 mg, 3.0 mmol) in 20 mL of dichloromethane were added TCDI (1.07 g, 3.6 mmol) and triethylamine (1.25 g, 12 mmol). The mixture was stirred at room temperature for 2 hours, followed by the addition of thiophen-3-ylmethylamine (339 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated to afford a crude residue, which was purified by preparative liquid phase to afford 1-(3-(dimethylamino)-4-methylbenzyl)-3-(thiophen-3-ylmethyl)thiourea as an off-white solid (Compound 1-2-2, 500 mg, 52% yield).

[0354] Example 20. Preparation of Compound 1-2-3 of the Present Invention

[0355] 1. Synthesis of compound 1-2-2

[0356] Compound 1-2-2 was synthesized with reference to Example 19.

[0357] 2. Synthesis of compound 188-1-2

[0358] To a solution of compound 1-2-2 (319 mg, 1 mmol) in 20 mL of acetonitrile was added iodomethane (800 mg, 6 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 residue, which was then purified by column chromatography (DCM / MeOH = 30 / 1) to afford methyl (Z)-N-(3-(dimethylamino)-4-methylbenzyl)-N'-(thiophen-3-ylmethyl)aminothiocarbamate (188-1-2, 200 mg, 60% yield) as a pale yellow oil.

[0359] 3. Synthesis of compound 1-2-3

[0360] Ammonia (600 mg, 6.0 mmol) was added to a 10 mL acetonitrile solution containing 188-1-2 (200 mg, 0.6 mmol) and stirred at 80°C overnight. After the reaction was complete, the reaction solution was concentrated to obtain a crude residue, which was purified by preparative liquid phase to obtain 1-(3-(dimethylamino)-4-methylbenzyl)-3-(thiophen-3-ylmethyl)guanidine (compound 1-2-3, 54.13 mg, 32% yield) as a white solid. MS Calcd.: 303.2 [M+H] +;MS Found:303.2[M+H] + .

[0361] 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).

[0362] Example 21. Preparation of Compound 1-2-119 of the Present Invention

[0363] 1. Synthesis of 188-6-2

[0364] To a 250 mL sealed tube, 188-6-1 (3.0 g, 19.35 mmol) and a solution of dimethylamine in tetrahydrofuran (2N, 100 mL) were added and reacted at 70°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by forward column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford 188-6-2 as a yellow oil (3.0 g, yield: 86%). MS Calcd.: 181.1 [M+H] + ;MS Found:181.3[M+H] + .

[0365] 2. Synthesis of 188-6-3

[0366] To a reaction flask, 188-6-2 (3.0 g, 16.67 mmol) was added and dissolved in methanol (170 mL). Pd / C (600 mg) was then added and the atmosphere was replaced with a hydrogen balloon three times. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. After completion of the reaction, the mixture was filtered and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain 188-6-3 as a yellow oil (2.2 g, 88% yield). MS Calcd.: 151.1 [M+H] + ;MS Found:151.4[M+H] + .

[0367] 3. Synthesis of 188-6-4

[0368] 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 stirred at room temperature for two hours. SM-1 (297 mg, 3.0 mmol) was then added to the system and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase purification to obtain 188-6-4 (610 mg, 69.9%) as a white solid. MS Calcd.: 292.1 [M+H] + ;MS Found:292.1[M+H] + .

[0369] 4. Synthesis of 188-6-5

[0370] 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. The tube was sealed and stirred at 40°C for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] afforded an off-white solid 188-6-5 (300 mg, 63.6%). MS Calcd.: 306.1 [M+H] + ;MS Found:306.1[M+H] + .

[0371] 5. Synthesis of 1-2-119

[0372] 188-6-5 (350 mg, 1.15 mmol) was added to a sealed tube and dissolved in acetonitrile (12 mL). Ammonia (2 mL) was then added and the tube was sealed and stirred at 80°C for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] afforded an off-white solid 1-2-119 (76.05 mg, 24%). MS Calcd.: 275.1 [M+H] + ;MS Found:275.4[M+H] + .

[0373] 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).

[0374] Example 22. Preparation of Compound 1-1-9 of the Present Invention

[0375] 1. Synthesis of Compound 192-1

[0376] Sodium hydride (2.42 g, 60.60 mmol) was slowly added to tetrahydrofuran (150 mL) at 0°C. Under nitrogen, 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. Iodomethane (8.6 g, 60.60 mmol) was then slowly added dropwise. The mixture was allowed to react at room temperature for 30 minutes. After the reaction was complete, the mixture was slowly poured into ice water and filtered. The filter cake was washed three times with water (5 mL) to obtain 192-1-2 (3.0 g, yield: 48.8%) as a brown solid.

[0377] 2. Synthesis of Compound 110-3

[0378] Compound 110-3 was synthesized according to Example 1.

[0379] 3. Synthesis of Compound 192-2

[0380] Compounds 192-1 (1.0 g, 4.93 mmol) and 110-3 (808 mg, 4.93 mmol) were added to a microwave tube and dissolved in ethanol (20 mL). The mixture was stirred and reacted at 78°C for 10 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] afforded the off-white solid 192-2 (1.0 g, yield: 63.7%). MS Calcd.: 320.1 [M+H] + ;MS Found:320.2[M+H] +

[0381] 4. Synthesis of compound 1-1-9

[0382] Compound 192-2 (230 mg, 0.72 mmol) and SM-1 (82 mg, 0.72 mmol) were placed in a single-necked flask and dissolved in ethanol (1 mL). Triethylamine (218 mg, 2.16 mmol) was then added and stirred at 78°C under a nitrogen atmosphere for two days. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] afforded 1-1-9 as an off-white solid (420 mg, 68%). MS Calcd.: 385.1 [M+H] + ;MS Found:385.4[M+H] + . .

[0383] 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).

[0384] Example 23. Preparation of Compound 1-1-1-B of the Present Invention

[0385] 1. Synthesis of compound 110-3

[0386] Compound 110-3 was synthesized according to Example 1.

[0387] 1. Synthesis of compound 1-1-1-B

[0388] To a solution of compound 110-3 (300 mg, 1.826 mmol) in tetrahydrofuran (10 mL) was added CDI (296.09 mg, 1.826 mmol) and stirred at 25°C for 0.5 hours. SM-16 (177.39 mg, 1.826 mmol) was then added and stirred at 80°C for 2.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by slurrying in acetonitrile to afford 1-1-1-B (157.8 mg, 30.07% yield) as an off-white solid. MS Calcd.: 288.1 [M+H] + ;MS Found:288.1[M+H] + .

[0389] 1H NMR(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).

[0390] Example 24. Preparation of Compound 1-1-14 of the Present Invention

[0391] 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 stirred at room temperature for two hours. 13-1-1 (200 mg, 1.33 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase preparation to obtain 1-1-14 (160 mg, yield: 41.6%) as a white solid. MS Calcd.: 290.1 ​​[M+H] + ;MS Found:290.4[M+H] + .

[0392] 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).

[0393] Example 25. Preparation of Compound 1-1-28 of the Present Invention

[0394] 1. Synthesis of compound 110-3

[0395] Compound 110-3 was synthesized according to Example 1.

[0396] 2. Synthesis of compound 1-1-28

[0397] 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 added to the reaction system and stirred at room temperature for two hours. 110-3 (720 mg, 4.39 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 0-3%) to afford 1-1-28 (405 mg, yield: 29%) as a pale yellow solid. MS Calcd.: 320.1 [M+H] + ;MS Found:320.4[M+H] + .

[0398] 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).

[0399] Example 26. Preparation of Compound 1-1-29 of the Present Invention

[0400] 1. Synthesis of compound 1-1-28

[0401] Compound 110-3 was synthesized according to Example 25.

[0402] 2. Synthesis of compound 1-1-29

[0403] 1-1-28 (280 mg, 0.88 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (10 mL). 7N aqueous ammonia (5 mL) and lead carbonate (596 mg, 2.19 mmol) were then added to the reaction system and stirred overnight at 80°C. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) and reverse phase preparative purification afforded 1-1-29 (143.92 mg, 54% yield) as a white solid.

[0404] 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).

[0405] Example 27. Preparation of Compound 1-1-40 of the Present Invention

[0406] 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 stirred at room temperature for two hours. SM-5 (226 mg, 2.0 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography afforded 1-1-40 (156 mg, 26% yield) as a white solid. MS Calcd.: 290.1 ​​[M+H] + ;MS Found:290.4[M+H] + .

[0407] 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).

[0408] Example 28. Preparation of Compound 1-1-41 of the Present Invention

[0409] 1. Synthesis of compound SM-6

[0410] SM-5 (2.05 mL, 20 mmol, 1.0 equiv.) was dissolved in EtOH (40 mL). Carbon disulfide (3.61 mL, 60 mmol, 3.0 equiv.) and triethylamine (2.78 mL, 20 mmol, 1.0 equiv.) were added at room temperature and allowed to react for 1 hour. DMAP (73 mg, 0.6 mmol, 0.03 equiv.) and Boc2O (4.6 mL, 20 mmol, 1.0 equiv.) were then added at 0°C. The mixture was then allowed to react overnight at room temperature. After the reaction was complete, the solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 40:1) to afford SM-6 (2.72 g, 88% yield) as a yellow oil.

[0411] 2. Synthesis of compound 1-1-41

[0412] 13-1-1 (180 mg, 1.2 mmol, 1.1 equiv) was weighed into a 10 mL flask, toluene (3 mL) and SM-6 (150 mg, 1.0 mmol, 1.0 equiv) were added, and the mixture was stirred at room temperature for 2 h. The reaction solution was purified by silica gel column chromatography (DCM) to obtain 1-1-41 (205 mg, 0.67 mmol, 66% yield) as a white solid. m / z: [M+H] + Calcd for C 15 H 19 N3S2H + 306.4655; Found 306.1108.

[0413] 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)

[0414] Example 29. Preparation of Compound 1-1-174 of the Present Invention

[0415] 1. Synthesis of compound 1-181-2

[0416] To a 250 mL sealed tube, 1-181-1 (2.0 g, 10.58 mmol) and dimethylamine tetrahydrofuran (2.0 N in THF, 70 mL) were added and stirred at 70°C for three days. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by forward column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford 1-181-2 as a yellow oil (2.0 g, yield: 88.0%). MS Calcd.: 215.1 [M+H] + ;MS Found:215.3[M+H] + .

[0417] 2. Synthesis of compound 1-181-3

[0418] To a reaction flask, 1-181-2 (1.0 g, 4.67 mmol) and THF (20 mL) were added. The mixture was replaced with a nitrogen balloon three times and cooled to 0°C in an ice bath. LAH (2.5N in THF, 3.74 mL, 9.34 mmol) was slowly added dropwise and stirred at room temperature overnight. After the reaction was complete, the system was cooled to 0°C and water (1 mL), 15% sodium hydroxide solution (1 mL), and water (3 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by forward column chromatography [dichloromethane:methanol (100:1-20:1)] to afford 1-181-3 as a yellow oil (700 mg, yield: 70%). MS Calcd.: 219.1 [M+H] + ;MS Found:219.3[M+H] + .

[0419] 3. Synthesis of compound 1-1-174

[0420] 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 stirred at room temperature for two hours. 1-181-3 (482 mg, 2.21 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase purification to obtain 1-1-174 (166.54 mg, yield: 21%) as a white solid. MS Calcd.: 357.1 [M+H] + ;MS Found:357.3[M+H] + .

[0421] 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).

[0422] Example 30. Preparation of Compound 1-2-14 of the Present Invention

[0423] 1. Synthesis of compound 13-2-1

[0424] 13-2-0 (2.4 g, 20 mmol), aqueous formaldehyde 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 added to the reaction system, and the reaction solution was stirred at room temperature overnight. 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, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound 13-2-1 (1.5 g, yield 51%) as a light yellow oil. MS Calcd.: 147.1 [M+H] + ;MS Found:147.2[M+H] + .

[0425] 2. Synthesis of compound 13-2-2

[0426] 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 solution was allowed to warm to room temperature and stirred overnight. After the reaction was complete, the reaction solution was quenched with water (1.0 mL), 15% aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL). The mixture was then filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford compound 13-2-2 (900 mg, 60% yield) as a pale yellow oil. MS Calcd.: 151.1 [M+H] + ;MS Found:151.2[M+H] + .

[0427] 3. Synthesis of compound 1-2-14

[0428] 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 stirred at room temperature for two hours. SM-1 (226 mg, 2.0 mmol) was then added to the system and allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography afforded 1-2-14 (159 mg, 28% yield) as a white solid. MS Calcd.: 290.1 ​​[M+H] + ;MS Found:290.2[M+H] + .

[0429] 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).

[0430] Example 31. Preparation of Compound 1-2-27 of the Present Invention

[0431] 1. Synthesis of 140-3

[0432] Compound 140-3 was synthesized according to Example 18.

[0433] 2. Synthesis of compound 1-2-27

[0434] 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 added to the system and stirred at room temperature for two hours. 140-3 (362 mg, 2.21 mmol) was then added to the system and allowed to react overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse synthesis afforded 1-2-27 (108.79 mg, 34%) as a white solid. MS Calcd.: 303.2 [M+H] + ;MS Found:303.4[M+H]+ .

[0435] 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).

[0436] Example 32. Preparation of Compound 1-2-28 of the Present Invention

[0437] 1. Synthesis of 140-3

[0438] Compound 140-3 was synthesized according to Example 18.

[0439] 2. Synthesis of compound 1-2-28

[0440] 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 stirred at room temperature for two hours. 140-3 (870 mg, 5.31 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse synthesis to obtain 1-2-28 (620 mg, 36%) as a white solid. MS Calcd.: 320.1 [M+H] + ;MS Found:320.2[M+H] + .

[0441] 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).

[0442] Example 33. Preparation of Compound 1-2-29 of the Present Invention

[0443] 1. Synthesis of 1-2-28

[0444] Compound 1-2-28 was synthesized with reference to Example 32.

[0445] 2. Synthesis of compound 1-2-28A

[0446] 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 mixture was stirred at 40°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1-5:1)] afforded an off-white solid 1-2-28A (300 mg, 90%). MS Calcd.: 334.2 [M+H] + ;MS Found:334.4[M+H] + .

[0447] 3. Synthesis of compound 1-2-29

[0448] 1-2-28A (300 mg, 0.9 mmol) was added to a sealed tube and dissolved in acetonitrile (15 mL). Ammonia (5 mL) was then added, and the tube was sealed and stirred at 80°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] and preparative liquid chromatography afforded an off-white solid, 1-2-29 (120.28 mg, 44%). MS Calcd.: 303.2 [M+H] + ;MS Found:303.4[M+H] + .

[0449] 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).

[0450] Example 34. Preparation of Compound 1-2-40 of the Present Invention

[0451] 1. Synthesis of 13-2-2

[0452] Compound 13-2-2 was synthesized with reference to Example 30.

[0453] 2. Synthesis of 1-2-40

[0454] 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 stirred at room temperature for two hours. SM-5 (226 mg, 2.0 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. 1-2-40 (163 mg, 28% yield) was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) and reverse preparative chromatography to obtain a white solid. MS Calcd.: 290.2 [M+H] + ;MS Found:290.2[M+H] + .

[0455] 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).

[0456] Example 35. Preparation of Compound 1-2-1-A1 of the Present Invention

[0457] 1. Synthesis of 140-3

[0458] Compound 140-3 was synthesized according to Example 18.

[0459] 2. Synthesis of 1-2-1-A1

[0460] To a solution of compound SM-32 (354.78 mg, 3.653 mmol) in tetrahydrofuran (10 mL) was added CDI (295.89 mg, 1.826 mmol), and the mixture was stirred at 25°C for 1 hour. Compound 140-3 (300 mg, 1.826 mmol) was then added and stirred at 80°C for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography to afford 1-2-1-A1 (264.2 mg, 50% yield) as a white solid. MS Calcd.: 288.2 [M+H]+ ;MS Found:288.1[M+H] + .

[0461] 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).

[0462] Example 36. Preparation of Compound 1-2-1-B1 of the Present Invention

[0463] 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 stirred at room temperature for 1 hour. 140-3 (1.69 g, 10.3 mmol) was added to the system and stirred at 80°C overnight. After the reaction was complete, the reaction solution was poured into 100 mL of water and extracted with dichloromethane (50 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. A small amount of ethyl acetate was added to slurry, filtered, and the filter cake was dissolved in a small amount of methanol and lyophilized in deionized water to obtain 1-2-1-B1 as a white solid (667.39 mg, yield: 22.5%). MS Calcd.: 288.2 [M+H] + ;MS Found:288.3[M+H] + .

[0464] 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).

[0465] Example 37. Preparation of Compound 2-1-1 of the Present Invention

[0466] 1. Synthesis of 1-3-4

[0467] SM-6 (500 mg, 4.35 mmol) was dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (600 mg, 5.22 mmol) was added dropwise in an ice bath. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction solution was poured into ice water to quench the mixture. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-3-4 (920 mg, yield: 100.00%). MS Calcd.: 194.0 [M+H] + ;MS Found:194.3[M+H]+.

[0468] 2. Synthesis of 1-3-5

[0469] Dissolve 1-3-4 (920 mg, 4.77 mmol) in DMF (10 mL), add potassium phthalimide (1.06 g, 5.72 mmol), and stir at room temperature for 1 hour. After completion, dilute with ethyl acetate, wash with ammonium chloride solution, water, and saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 / 1 to 2 / 1) to obtain compound 1-3-5 (930 mg, yield: 80%). MS Calcd.: 245.0 [M+H] + ;MS Found:245.3[M+H] +

[0470] 3. Synthesis of SM-7

[0471] 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 reaction was stirred at 80°C for 30 minutes. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, diluted with dichloromethane, poured into water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 2 / 1) to afford compound SM-7 (2.2 g, yield: 83%).

[0472] 4. Synthesis of Compound 110-3

[0473] Compound 110-3 was synthesized according to Example 1.

[0474] 5. Synthesis of 2-1-1

[0475] SM-7 (300 mg, 2.63 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (1.06 g, 10.53 mmol) and CDI (639 mg, 3.95 mmol) were added to the mixture and stirred at room temperature for two hours. 110-3 (648 mg, 3.95 mmol) was then added to the mixture and allowed to react overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse synthesis afforded 2-1-1 (177.87 mg, 22%) as a white solid. MS Calcd.: 305.1 [M+H] + ;MS Found:305.1[M+H] + .

[0476] 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).

[0477] Example 38. Preparation of Compound 2-1-2 of the Present Invention

[0478] 1. Synthesis of compound 110-3

[0479] Compound 110-3 was synthesized according to Example 1.

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

[0481] 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 stirred at room temperature for two hours. SM-8 (228 mg, 2.0 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and reverse phase preparative purification afforded 2-1-2 as an off-white solid (152.15 mg, yield: 25.6%). MS Calcd.: 305.1 [M+H] +;MS Found:305.1[M+H] + .

[0482] 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),6.58(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).

[0483] Example 39. Preparation of Compound 2-1-3 of the Present Invention

[0484] 1. Synthesis of compound 110-3

[0485] Compound 110-3 was synthesized according to Example 1.

[0486] 2. Synthesis of 2-1-3

[0487] 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 stirred at room temperature for two hours. SM-9 (228 mg, 2.0 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and reverse phase preparative purification afforded 2-1-3 as an off-white solid (158.01 mg, yield: 26%). MS Calcd.: 305.1 [M+H] + ;MS Found:305.4[M+H] + .

[0488] 1 H 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),6.8 3-6.81(m,3H),6.51(t,J=5.6Hz,2H),4.50(d,J=6.4Hz,2H),4.25(d,J=6.0Hz,2H),2.60(s,6H),2.26(s,3H).

[0489] Example 40. Preparation of Compound 3-1-1 of the Present Invention

[0490] 1. Synthesis of compound 3-1-1-2

[0491] 3-1-1-1 (2.6 g, 20.0 mmol) was added to a reaction flask and dissolved in tert-butanol (50 mL). Triethylamine (2.02 g, 20.0 mmol) and DPPA (5.5 g, 20.0 mmol) were added to the reaction system, and the reaction solution was stirred at 80°C overnight. After the reaction was complete, the mixture was cooled to room temperature, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) afforded 13-1-1-2 (1.8 g, yield: 45%) as a pale yellow solid. MS Calcd.: 201.1 [M+H] + ;MS Found:202.2[M+H] + .

[0492] 2. Synthesis of compound 3-1-1-3

[0493] 3-1-1-2 (1.8 g, 9.0 mmol) was added to the reaction flask and dissolved in 4N hydrochloric acid in dioxane (50 mL). The reaction mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a white solid SM-10 (1.2 g, yield: 98%). MS Calcd.: 101.0 [M] + ;MS Found:101.3[M] + .

[0494] 3. Synthesis of 280-3

[0495] Compound 280-3 was synthesized according to Example 13.

[0496] 4. Synthesis of compound 3-1-1

[0497] 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 stirred at room temperature for 4 hours. 280-3 (408 mg, 3.0 mmol) was then added to the system and stirred at 45°C overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and preparative liquid chromatography afforded 3-1-1 as an off-white solid (131.88 mg, yield: 17.5%).

[0498] 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).

[0499] Example 41. Preparation of Compound 3-1-2 of the Present Invention

[0500] 1. Synthesis of SM-7

[0501] Compound SM-7 was synthesized according to Example 36.

[0502] 2. Synthesis of 3-1-2

[0503] 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 added to the reaction system and stirred at room temperature for two hours. 13-1-1 (290 mg, 1.93 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and preparative liquid chromatography afforded 3-1-2 (158.31 mg, yield: 28%) as a white solid. MS Calcd.: 291.1 [M+H] + ;MS Found:291.3[M+H] + .

[0504] 1H NMR (400 MHz, CD3OD) δ8.38 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 7.2 Hz, 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). Example 42. Preparation of Compound 3-1-3 of the Present Invention

[0505] 1. Synthesis of compound 110-3

[0506] Compound 110-3 was synthesized according to Example 1.

[0507] 2. Synthesis of 3-1-3

[0508] 110-3 (250 mg, 1.52 mmol) was added to the reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (462 mg, 4.57 mmol) and CDI (246 mg, 1.52 mmol) were added to the reaction system and stirred at room temperature for two hours. SM-11 (149 mg, 1.52 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0 ～ 3%) purified white solid 3-1-3 (56.35 mg, yield: 13%). MS Calcd.: 289.2 [M+H] + ;MS Found:289.2[M+H] + .

[0509] 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).

[0510] Example 43. Preparation of Compound 3-1-4 of the Present Invention

[0511] 1. Synthesis of compound 110-3

[0512] Compound 110-3 was synthesized according to Example 1.

[0513] 2. Synthesis of 3-1-4

[0514] To a solution of 110-3 (328 mg, 2.0 mmol) in dichloromethane (20 mL) were added CDI (486 mg, 3.0 mmol) and triethylamine (1.0 g, 10.0 mmol). The resulting mixture was stirred at room temperature for two hours, followed by the addition of SM-12 (340 mg, 2.0 mmol) and continued stirring at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to afford the crude product, which was purified by preparative liquid chromatography to afford 3-1-4 as a white solid (116.92 mg, 20% yield).

[0515] 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).

[0516] Example 44. Preparation of Compound 3-1-5 of the Present Invention

[0517] 1. Synthesis of Compound 103-1

[0518] 104-2A (485 mg, 2.37 mmol) was dissolved in 40 mL of dimethylamine, and the mixed solution was stirred at 70°C for 3 days. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to afford 103-1 (387 mg, 80% yield). MS Calcd.: 231.1 [M+H] + ;MS Found:231.3[M+H] +

[0519] 2. Synthesis of Compound 103-2

[0520] To a solution of 103-1 (387 mg, 1.68 mmol) in methanol (20 mL) was added Pd / C (50 mg), and the mixed solution was stirred at room temperature overnight under a 0.5 MPa hydrogen atmosphere. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to afford 103-2 (232 mg, 80% yield) as a yellow solid. MS Calcd.: 233.1 [M+H] + ;MS Found:233.4[M+H] +

[0521] 3. Synthesis of Compound 103-3

[0522] To a solution of 103-2 (232 mg, 1.0 mmol) in methanol (20 mL) was added Riney Ni (50 mg), and the mixed solution was stirred at room temperature overnight under a 0.5 MPa hydrogen atmosphere. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford 103-3 (118 mg, 50% yield) as a yellow solid. MS Calcd.: 237.2 [M+H] + ;MS Found:237.4[M+H] +

[0523] 4. Synthesis of compound 3-1-5

[0524] To a solution of 103-3 (170 mg, 0.72 mmol) in dichloromethane (10 mL) were added CDI (178 mg, 1.1 mmol) and triethylamine (363 mg, 3.6 mmol). The resulting mixed solution was stirred at room temperature for 2 hours, followed by the addition of SM-1 (81 mg, 0.72 mmol). The resulting mixed solution was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to afford 3-1-5 as a white solid (50.33 mg, 48.5% yield). MS Calcd.: 376.2 [M+H] + ;MS Found:376.3 [M+H] +

[0525] 1 H 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).

[0526] Example 45. Preparation of Compound 3-1-6 of the Present Invention

[0527] 1. Synthesis of Compound 104-8

[0528] To a solution of 104-2A (1.0 g, 4.88 mmol) in methanol / water (24 / 6 mL) was added lithium hydroxide (615 mg, 14.63 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 a pH of approximately 6, and filtered to obtain the crude product. Silica gel column chromatography afforded 104-8 (750 mg, 80% yield) as a white solid.

[0529] 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)

[0530] 2. Synthesis of Compound 104-9

[0531] 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 continued stirring overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to afford 104-9 (480 mg, 50% yield) as a white solid.

[0532] 3. Synthesis of Compound 104-10

[0533] 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, it was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–2.5%) to give 104-10 (370 mg, 69% yield) as a yellow solid. MS Calcd.: 230.1 [M+H] + ;MS Found:230.3[M+H] + .

[0534] 4. Synthesis of Compound 104-7

[0535] To a solution of 104-10 (340 mg, 1.47 mmol) in ethanol (20 mL) was added Pd / C (68 mg), and the mixed solution was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford 104-7 (300 mg, 88% yield) as a yellow solid. MS Calcd.: 232.1 [M+H] + ;MS Found:232.3[M+H] + .

[0536] 5. Synthesis of Compound 104-11

[0537] To a solution of 104-7 (300 mg, 1.30 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (2.6 mmol) at zero degrees Celsius, and the mixed solution was stirred at room temperature overnight. 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 mixed solution was stirred at room temperature for 20 minutes. The mixed solution was filtered to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford 104-11 (120 mg, 40% yield) as a yellow solid. MS Calcd.: 236.1 [M+H] + ;MS Found:236.4[M+H] + .

[0538] 6. Synthesis of compound 3-1-6

[0539] To a solution of 104-11 (169 mg, 0.72 mmol) in dichloromethane (10 mL) were added CDI (178 mg, 1.1 mmol) and triethylamine (363 mg, 3.6 mmol). The resulting mixed solution was stirred at room temperature for 2 hours, followed by the addition of SM-1 (81 mg, 0.72 mmol). The resulting mixed solution was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to afford 3-1-6 (88 mg, 33% yield) as a white solid. MS Calcd.: 375.2 [M+H] + ;MS Found:375.4[M+H] +

[0540] 1H 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).

[0541] Example 46. Preparation of Compound 3-1-7 of the Present Invention

[0542] 1. Synthesis of compound 110-3

[0543] Compound 110-3 was synthesized according to Example 1.

[0544] 2. Synthesis of compound 3-1-7

[0545] To a solution of 110-3 (164 mg, 1.0 mmol) in DMF (10 mL) were added CDI (243 mg, 1.5 mmol) and triethylamine (500 mg, 5.0 mmol). The resulting mixed solution was stirred at room temperature for 2 hours, followed by the addition of SM-13 (99 mg, 1.0 mmol). The resulting mixed solution was stirred at 80°C overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to afford 3-1-7 (117 mg, 40% yield) as a white solid. MS Calcd.: 290.2 [M+H] + ;MS Found:290.1[M+H] + .

[0546] 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).

[0547] Example 47. Preparation of Compound 3-1-8 of the Present Invention

[0548] 1. Synthesis of compound 18-2

[0549] To a solution of 4-chloro-3,5-dinitrobenzoic acid (18-1, 9.8 g, 40 mmol) in methanol (500 mL) was added potassium hydroxide (4.48 g, 80 mmol), and the resulting mixture was stirred at 70°C for 20 hours. After completion, the reaction was quenched by the addition of 500 mL of 3N hydrochloric acid. 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 yield the crude product. Purification by silica gel column chromatography afforded 18-2 as a light yellow solid (8.2 g, 85% yield).

[0550] 2. Synthesis of Compound 18-11

[0551] To a solution of 4-methoxy-3,5-dinitrobenzoic acid (18-2, 8.2 g, 34 mmol) in methanol (250 mL) was added concentrated sulfuric acid (10 mL), 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 yield the crude product. Purification by silica gel column chromatography afforded 18-11 as a light yellow oil (4.8 g, 55% yield).

[0552] 3. Synthesis of Compound 18-12

[0553] To a solution of methyl 4-methoxy-3,5-dinitrobenzoate (18-11, 4.8 g, 18.8 mmol) in ethanol (200 mL) was added Pd / C (960 mg). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to afford 18-12 as a light yellow oil (8.2 g, 85% yield).

[0554] 4. Synthesis of Compound 18-13

[0555] To a solution of methyl 4-methoxy-3,5-diaminobenzoate (18-12, 3.0 g, 15.3 mmol), aqueous formaldehyde (11.5 g, 153 mmol), and acetic acid (10 mL) in methanol (30 mL) was added NaBH3CN (5.7 g, 91.8 mmol). The resulting mixture was stirred at room temperature for 20 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 afford 18-13 as a light brown oil (2.5 g, 65% yield).

[0556] 5. Synthesis of Compound 18-14

[0557] 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-bis(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. After filtration and concentration under reduced pressure, the crude product was obtained. Purification by column chromatography afforded 18-14 as a yellow oil (1.7 g, 77% yield).

[0558] 6. Synthesis of Compound 18-15

[0559] 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) were added DEAD (5.29 g, 30.4 mmol) and PPh3 (3.0 g, 11.4 mmol). 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 the crude product, which was purified by column chromatography to afford 18-15 (1.5 g, 56% yield) as a yellow oil.

[0560] 7. Synthesis of Compound 18-6

[0561] To a solution of 18-15 (1.5 g, 4.2 mmol) in ethanol (30 mL) was added hydrazine hydrate (353 mg, 8.4 mmol), 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 afford the crude product, which was purified by column chromatography (DCM / MeOH = 20 / 1) to afford 18-6 (700 mg, 75% yield) as a light brown oil.

[0562] 8. Synthesis of compound 3-1-8

[0563] To a solution of 18-6 (200 mg, 0.9 mmol) in dichloromethane (20 mL) were added CDI (220 mg, 1.35 mmol) and triethylamine (455 mg, 4.5 mmol). 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 at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to afford 3-1-8 as a light brown oil (102 mg, 31% yield). MS Calcd.: 363.2 [M+H] + ;MS Found:363.2[M+H] + .

[0564] 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).

[0565] Example 48. Preparation of Compound 3-1-9 of the Present Invention

[0566] 1. Synthesis of compound 21-2

[0567] To a solution of 21-1 (1.66 g, 10 mmol) and phenol (1.04 g, 11 mmol) in tetrahydrofuran (50 mL) was added 60% sodium hydride (400 mg, 10 mmol), and the resulting mixture was 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 afford 21-2 (2.0 g, 83% yield) as a light yellow solid.

[0568] 2. Synthesis of Compound 21-3

[0569] To a solution of 21-2 (480 mg, 2.0 mmol) in ethanol (20 mL) was added Pd / C (96 mg), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to afford 21-3 (400 mg, 95% yield) as a light yellow oil.

[0570] 3. Synthesis of Compound 21-4

[0571] To a solution of 21-3 (400 mg, 1.9 mmol), formaldehyde (2.85 g, 38 mmol), and acetic acid (3 mL) in methanol (10 mL) was added NaBH3CN (1.2 g, 19 mmol). 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 a pH of approximately 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 afford 21-4 (300 mg, 66% yield) as a light brown oil.

[0572] 4. Synthesis of Compound 21-5

[0573] Under nitrogen protection and an ice-water bath, lithium aluminum hydride (2.5N tetrahydrofuran solution, 1.0 mL) was added to a solution of 21-4 (2.5 g, 9.9 mmol) in diethyl ether (20 mL). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, H₂O (0.2 mL), 15% NaOH solution (0.2 mL), and H₂O (0.6 mL) were added sequentially. After filtration and concentration under reduced pressure, the crude product was obtained. Purification by column chromatography afforded 21-5 as a yellow oil (200 mg, 66% yield).

[0574] 5. Synthesis of compound 3-1-9

[0575] To a solution of 21-5 (200 mg, 0.83 mmol) in dichloromethane (20 mL) were added CDI (207 mg, 1.25 mmol) and triethylamine (420 mg, 4.15 mmol). The mixture was stirred at room temperature for 2 hours, followed by the addition of SM-5 (94 mg, 0.83 mmol). The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to afford 3-1-9 as a white solid (190 mg, 60% yield). MS Calcd.: 382.2 [M+H] + ;MS Found:382.4[M+H] + .

[0576] 1 H 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).

[0577] Example 49. Preparation of Compound 3-1-10 of the Present Invention

[0578] 1. Synthesis of compound 19-2

[0579] 19-1 (600 mg, 4.55 mmol) was added to a reaction flask and dissolved in methanol (25 mL). Then, aqueous formaldehyde (3.69 g, 45.5 mmol), acetic acid (1.37 g, 22.75 mmol), and sodium cyanoborohydride (1.43 g, 22.75 mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen atmosphere overnight. After completion, the reaction was quenched with water (40 mL) and extracted three times with dichloromethane (40 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by column chromatography (petroleum ether:ethyl acetate (20:1-5:1)) afforded 19-2 as a yellow oil (560 mg, yield: 77%). MS Calcd.: 161.1 [M+H] + ;MS Found:161.4[M+H] + .

[0580] 2. Synthesis of Compound 19-3

[0581] To a reaction flask, 19-2 (560 mg, 3.50 mmol) and tetrahydrofuran (15 mL) were added, the atmosphere was replaced three times with a nitrogen balloon, and the mixture was cooled to 0°C under a nitrogen atmosphere. Lithium aluminum hydride (2.5N in THF, 7.0 mmol, 2.8 mL) was then added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was complete, the system was cooled to 0°C, and water (0.6 mL), 15% aqueous sodium hydroxide solution (0.6 mL), and water (1.8 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by forward column chromatography [dichloromethane:methanol (100:1-20:1)] to afford 19-3 as a yellow oil (300 mg, yield: 52%). MS Calcd.: 164.2 [M+H] + ;MS Found:164.4[M+H] + .

[0582] 3. Synthesis of SM-7

[0583] Compound SM-7 was synthesized according to Example 36.

[0584] 4. Synthesis of compound 3-1-10

[0585] 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 added to the mixture and stirred at room temperature for two hours. 19-3 (300 mg, 1.83 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reverse synthesis to obtain 3-1-10 (170.65 mg, 31% yield) as a white solid.

[0586] 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).

[0587] Example 50. Preparation of Compound 3-1-11 of the Present Invention

[0588] 1. Synthesis of Compound 48-1

[0589] To a solution of 48-1 (290 mg, 1.0 mmol) and triethylamine (404 mg, 4.0 mmol) in methanol (20 mL) was added Pd(dppf)Cl2 (73 mg, 0.1 mmol), and the resulting mixture was stirred at 80°C overnight under a CO atmosphere. After the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative liquid chromatography to afford 48-2 as a white solid (200 mg, 74% yield).

[0590] 2. Synthesis of compound 48-3

[0591] 48-2 (200 mg, 0.74 mmol) was added to 10 mL of 4N hydrochloric acid in dioxane and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give 48-3 (150 mg, 93% yield) as a yellow solid.

[0592] 3. Synthesis of Compound 110-3

[0593] Compound 110-3 was synthesized according to Example 1.

[0594] 4. Synthesis of compound 3-1-11

[0595] To a solution of 110-3 (118 mg, 0.72 mmol) in dichloromethane (10 mL) were added CDI (178 mg, 1.1 mmol) and triethylamine (363 mg, 3.6 mmol). 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 at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to afford 3-1-11 as a white solid (98 mg, 52% yield). MS Calcd.: 362.2 [M+H] + ;MS Found:362.4[M+H] + .

[0596] 1 H 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).

[0597] Example 51. Preparation of Compound 3-1-12 of the Present Invention

[0598] 1. Synthesis of Compound T1-2

[0599] To a reaction flask, add T1-1 (2.0 g, 14.26 mmol) and dissolve in DMF (40 mL). Then, add NBS (2.54 g, 14.26 mmol) to the reaction system and stir overnight at room temperature. After the reaction is complete, dilute with water (50 mL) and extract with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated sodium chloride (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5%) to afford compound T1-2 (3.00 g, 96% yield) as a colorless oil.

[0600] 1H 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).

[0601] 2. Synthesis of Compound T1-3

[0602] TI-2 (2.50 g, 11.41 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (40 mL). The atmosphere was purged with nitrogen three times, then the reaction system was cooled to -78°C and LDA (1N, 11 mL, 11.41 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to react 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 extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5%) to afford compound T1-3 (2.00 g, 80% yield) as a colorless oil.

[0603] 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).

[0604] 3. Synthesis of Compound T1-4

[0605] To a reaction flask, add T1-3 (700 mg, 2.92 mmol) and dissolve in NMP (10 mL). Zn(CN)2 (343 mg, 2.92 mmol) and Pd(PPh3)4 (6.75 mg, 5.84 mmol) were then added. 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 solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10%) to afford compound T1-4 (350 mg, 73% yield) as a colorless oil. ESI [M+H] + =183.2.

[0606] 4. Synthesis of Compound T1-5

[0607] T1-4 (300 mg, 1.82 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (10 mL). BH3·THF (1N, 4 mL, 3.63 mmol) was then added to the reaction system and 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 (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 50%) to afford compound T1-5 (200 mg, 65% yield) as a colorless oil. ESI[M-16] + =153.3.

[0608] 5. Synthesis of Compound 110-3

[0609] Compound 110-3 was synthesized according to Example 1.

[0610] 6. Synthesis of compound 3-1-12

[0611] 110-3 (40g, 2.48mmol) was added to a reaction flask and dissolved in dichloromethane (40mL). Triethylamine (1.00g, 9.92mmol) and CDI (402mg, 2.48mmol) were then added to the reaction system and stirred at room temperature for two hours. T1-5 (420mg, 2.48mmol) was then added to the system and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. 3-1-12 (210mg, 24% yield) was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse phase preparative chromatography to obtain a white solid 3-1-12 (240mg, yield). MS Calcd.: 360.3[M+H] + ;MS Found:359.9[M+H] + .

[0612] 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).

[0613] Example 52: Preparation of Compound 3-1-13 of the Present Invention

[0614] 1. Synthesis of compound T4-6

[0615] T4-5 (2.8 g, 20.0 mmol) was added to a reaction flask and dissolved in acetic acid (100 mL). Bromine (9.6 g, 60 mmol) was then slowly added to the reaction system and stirred at 65°C for 2 days. After the reaction was complete, the mixture was diluted with ice water (300 mL), sodium thiosulfate was added to destroy the bromine, and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain compound T4-6 (5.0 g, 66% yield) as a colorless oil.

[0616] 2. Synthesis of compound T4-2

[0617] T4-6 (2.5 g, 6.7 mmol) was added to a reaction flask and dissolved in THF (100 mL). The atmosphere was replaced with nitrogen three times, then the reaction system was cooled to -78°C and 2.5N 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, 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 purified by silica gel column chromatography (petroleum ether) to obtain compound T4-2 (500 mg, 34% yield) as a colorless oil.

[0618] 3. Synthesis of compound T4-3

[0619] T4-2 (500 mg, 2.3 mmol) was added to a reaction flask and dissolved in NMP (10 mL). Zn(CN)2 (538 mg, 4.6 mmol) and Pd(PPh3)4 (265 mg, 0.23 mmol) were then added. The reaction mixture was heated to 150°C in a microwave reactor for 1 hour. After completion, 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 (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5%) to afford compound T4-3 (500 mg, 100% yield) as a pale yellow oil.

[0620] 4. Synthesis of Compound T4-4

[0621] T4-3 (500 mg, 3.03 mmol) was added to a reaction flask and dissolved in THF (20 mL). 2.5N lithium aluminum hydride (2.4 mL, 6.06 mmol) was then added to the reaction system at 0°C. After the addition was complete, the mixture was slowly warmed 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. After stirring for 30 minutes, the mixture was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to afford compound T4-4 (110 mg, 21.6% yield) as a pale yellow oil.

[0622] 5. Synthesis of Compound 110-3

[0623] Compound 110-3 was synthesized according to Example 1.

[0624] 6. Synthesis of compound 3-1-13

[0625] 110-3 (107 mg, 0.65 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Triethylamine (197 mg, 1.95 mmol) and CDI (116 mg, 0.72 mmol) were then added to the reaction system and stirred at room temperature for two hours. T4-4 (110 mg, 0.65 mmol) was then added to the system and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. 3-1-13 was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse phase preparative chromatography to afford 3-1-13 as a white solid (116.36 mg, yield: 50%). MS Calcd.: 360.3 [M+H] + ;MS Found:360.2[M+H] + .

[0626] 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).

[0627] Example 53. Preparation of Compound 3-1-14 of the Present Invention

[0628] 1. Synthesis of compound T7-2

[0629] 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 portionwise to the reaction mixture at 0°C. After the addition was complete, the temperature was slowly warmed 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 at room temperature overnight. After the reaction was complete, the mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10%) to afford compound T7-2 (~1.5 g, 67% yield) as a pale yellow oil.

[0630] 2. Synthesis of compound T7-5

[0631] T7-2 (896 mg, 4 mmol) was added to a 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 then added sequentially to the reaction mixture. After the addition was complete, the temperature was raised 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 (40 mL x 2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10%) to afford compound T7-5 (~500 mg, 62% yield) as a pale yellow oil. MS Calcd.: 203.3 [M+H] + ;MS Found:203.2[M+H] + .

[0632] 3. Synthesis of compound T7-4

[0633] T7-5 (500 mg, 2.5 mmol) was added to a reaction flask and dissolved in THF (20 mL). 2.5N lithium aluminum hydride (2.0 mL, 5.0 mmol) was then added to the reaction system at 0°C. After the addition was complete, the mixture was slowly warmed 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 in sequence. After stirring for 30 minutes, anhydrous magnesium sulfate (20 g) was added for drying, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to afford compound T7-4 (280 mg, 53% yield) as a pale yellow oil. MS Calcd.: 207.2 [M+H] + ;MS Found:207.3[M+H] + .

[0634] 4. Synthesis of compound 3-1-14

[0635] 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 stirred at room temperature for two hours. SM-1 (154 mg, 1.36 mmol) was then added to the system and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse phase preparative purification afforded 3-1-14 (125.06 mg, yield: 27%) as an off-white solid. MS Calcd.: 346.2 [M+H] + ;MS Found:346.2[M+H] + .

[0636] 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).

[0637] Example 54. Preparation of Compound 3-1-15 of the Present Invention

[0638] 1. Synthesis of compound 163-2

[0639] To a 250 mL reaction flask, 163-1 (1.0 g, 7.41 mmol) and piperidine (10 mL) were added and stirred at 80°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by forward column chromatography [petroleum ether:ethyl acetate (100:1-10:1)] to afford 163-2 as a brown oil (1.2 g, yield: 81%). MS Calcd.: 201.1 [M+H] + ;MS Found:201.4[M+H] + .

[0640] 2. Synthesis of compound 163-3

[0641] To a reaction flask, 163-2 (602 mg, 3.01 mmol) and Et2O (20 mL) were added. The atmosphere was replaced three times with a nitrogen balloon and cooled to 0°C under a nitrogen atmosphere. LAH (2.5N in THF, 2.4 mL) was then added and stirred at room temperature overnight. After completion of the reaction, water (1 mL), 15% NaOH (3 mL), and water (3 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. This was then purified by forward column chromatography (dichloromethane:methanol 20:1) to afford 163-3 as a yellow oil (2.0 g, 61% yield).

[0642] 3. Synthesis of compound 3-1-15

[0643] Compound 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 mixture and stirred at room temperature for two hours. SM-1 (122 mg, 1.08 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase purification to afford 3-1-15 (125.06 mg, 34%) as a white solid. MS Calcd.: 344.2 [M+H] + ;MS Found:344.4[M+H] + .

[0644] 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).

[0645] Example 55. Preparation of Compound 3-1-16 of the Present Invention

[0646] 1. Synthesis of compound 23-A1-3

[0647] 23-A1-5 (2.0 g, 14.8 mmol) and diethylamine (4.32 g, 59.2 mmol) were added to a sealed reaction tube and dissolved in methylpyrrolidone (50 mL). The reaction mixture was stirred at 140°C overnight. After the reaction was complete, the mixture was cooled to room temperature and slowly added with water (50 mL). The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 12%) afforded 23-A1-3 as a light yellow oil (1.1 g, yield: 40%). MS Calcd.: 189.1 [M+H] + ;MS Found:189.4[M+H] + .

[0648] 2. Synthesis of compound 23-A1-4

[0649] 23-A1-3 (1.1 g, 5.85 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (50 mL). 2.5N 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 mixture. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography [dichloromethane:methanol (0% to 15%)] afforded 23-A1-4 (400 mg, yield: 36%) as a light yellow oil. MS Calcd.: 193.2 [M+H] + ;MS Found:193.3[M+H] + .

[0650] 3. Synthesis of compound 3-1-16

[0651] SM-1 (237 mg, 2.08 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (822 mg, 10.4 mmol) and CDI (337 mg, 2.08 mmol) were added to the reaction system and stirred at room temperature for two hours. 23-A1-4 (400 mg, 2.08 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and preparative liquid chromatography afforded 3-1-16 as an off-white solid (134.70 mg, yield: 20%). MS Calcd.: 332.2 [M+H] + ;MS Found:332.2[M+H] + .

[0652] 1 H 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).

[0653] Example 56. Preparation of Compound 3-1-17 of the Present Invention

[0654] 1. Synthesis of Compound 199-7

[0655] 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 atmosphere was replaced with nitrogen three times, and the reaction was stirred at 80°C overnight under a nitrogen atmosphere. After completion of the reaction, the solvent was evaporated under reduced pressure, and 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 evaporated under reduced pressure to obtain the residue. The residue was purified by forward column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to obtain 199-7 (1.5 g, yield: 47%) as a yellow oil. MS Calcd.: 265.1 [M+H] + ;MS Found:265.4[M+H] + .

[0656] 2. Synthesis of Compound 199-8

[0657] To a 250 mL sealed tube, 199-7 (1.5 g, 5.68 mmol) and dimethylamine tetrahydrofuran (60 mL) were added and stirred at 70°C for two days. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by forward column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford 199-8 as a yellow oil (1.3 g, yield: 79%). MS Calcd.: 290.1 ​​[M+H] + ;MS Found:290.4[M+H] + .

[0658] 3. Synthesis of Compound 199-4

[0659] 199-8 (600 mg, 2.08 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added dropwise at room temperature and allowed to react for one hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a residue, which was dissolved in dichloromethane and poured into water. The pH was adjusted to 9 with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a residue. The residue was purified by forward column chromatography [dichloromethane:methanol (100:1-5:1)] to obtain 199-4 (200 mg, yield: 51%) as a yellow oil. MS Calcd.: 190.1 [M+H] + ;MS Found:190.2[M+H] + .

[0660] 4. Synthesis of Compound 199-5

[0661] SM-15 (200 mg, 1.06 mmol) was added to a reaction flask and dissolved in DMF (5 mL). Compound 199-4 (162 mg, 1.59 mmol), DIPEA (410 mg, 3.18 mmol), and EDCI (305 mg, 1.59 mmol) were then added sequentially. The reaction was stirred at room temperature under nitrogen for two hours. HOBT (215 mg, 1.59 mmol) was then added and allowed to react overnight at room temperature. After completion, 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), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a residue. The residue was purified by column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to afford compound 199-5 as a yellow oil (60 mg, yield: 30%). MS Calcd.: 161.1 [M+H] + ;MS Found:161.4[M+H] + .

[0662] 5. Synthesis of Compound 199-6

[0663] 199-5 (3.0 g, 22.73 mmol) was added to an autoclave and dissolved in methanol (100 mL). Raney-Ni (7.2 g, 113.65 mmol) was then added. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. After completion of the reaction, the mixture was filtered and the solvent was evaporated under reduced pressure to obtain a residue. The residue was purified by a forward column chromatography [dichloromethane:methanol (20:1-5:1)] to obtain 199-6 (3.2 g, yield: 89.9%) as a yellow oil. MS Calcd.: 278.2 [M+H] + ;MS Found:278.4[M+H] + .

[0664] 6. Synthesis of compound 3-1-17

[0665] 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 added to the system and stirred at room temperature for two hours. 199-6 (60 mg, 0.22 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase preparation to obtain 3-1-17 (18.32 mg, 20%) as a white solid. MS Calcd.: 417.1 [M+H] + ;MS Found:417.3[M+H] + .

[0666] 1 H 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).

[0667] Example 57. Preparation of Compound 3-1-18 of the Present Invention

[0668] 1. Synthesis of Compound 125-1

[0669] 110-1 (3.0 g, 22.2 mmol) was added to a reaction flask and dissolved in 2N methylamine (100 mL). The reaction was stirred at 70°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a residue, which was purified by a forward column chromatography (petroleum ether:ethyl acetate 5:1) to obtain a yellow solid 125-1 (3.0 g, yield: 94%). MS Calcd.: 147.1 [M+H] + ;MS Found:147.3[M+H] +

[0670] 2. Synthesis of compound 125-2

[0671] To a reaction flask, 125-1 (1.0 g, 6.85 mmol) and diethyl ether (20 mL) were added. Lithium aluminum hydride (13.70 mmol) was added to the system at 0°C and 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. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography (dichloromethane:methanol 20:1) afforded 125-2 (600 mg, 58% yield) as a yellow solid.

[0672] 3. Synthesis of compound 3-1-18

[0673] SM-1 (220 mg, 1.95 mmol) and dichloromethane (20 mL) were added to the reaction flask. CDI (473 mg, 2.92 mmol) and triethylamine (591 mg, 5.85 mmol) were then added to the system and stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by preparative liquid chromatography to obtain a white solid 3-1-18 (116 mg, 20% yield). MS Calcd.: 290.1 ​​[M+H] + ;MS Found:290.4[M+H] + .

[0674] 1H 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).

[0675] Example 58. Preparation of Compound 3-1-19 of the Present Invention

[0676] 1. Synthesis of 140-3

[0677] Compound 140-3 was synthesized according to Example 18.

[0678] 2. Synthesis of 3-1-19

[0679] To a solution of compound SM-12 (350 mg, 3.604 mmol) in tetrahydrofuran (10 mL) was added CDI (1751.44 mg, 10.811 mmol) and the mixture was stirred at room temperature for 2 hours. Compound 140-3 (1183.84 mg, 7.208 mmol) and 2-[ethyl(2-hydroxyethyl)amino]ethanol-1-ol (2 mL, 15.256 mmol) were then added and the mixture was stirred at 80°C for 14 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate (20 mL x 3), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by preparative liquid chromatography afforded compound 3-1-19 (157.5 mg, 15.21% yield) as a white solid. MS Calcd.: 288.4 [M+H] + ;MS Found:288.2[M+H] + .

[0680] 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).

[0681] Example 59. Preparation of Compound 3-1-20 of the Present Invention

[0682] 1. Synthesis of 280-3

[0683] Compound 280-3 was synthesized according to Example 13.

[0684] 2. Synthesis of 3-1-20

[0685] To a solution of compound 280-3 (1.94 g, 19.971 mmol) in tetrahydrofuran (20 mL) was added CDI (3.24 g, 19.971 mmol), and the mixture was stirred at room temperature for 2 hours. Compound SM-12 (1.5 g, 9.985 mmol) and 2-[ethyl(2-hydroxyethyl)amino]ethanol-1-ol (2 mL, 15.256 mmol) were then 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 brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by preparative liquid chromatography afforded compound 3-1-20 (269.1 mg, yield, 9.86%) as a white solid. MS Calcd.: 274.3 [M+H] + ;MS Found:274.1[M+H] + .

[0686] 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).

[0687] Example 60. Preparation of Compound 3-1-21 of the Present Invention

[0688] 1. Synthesis of 280-3

[0689] Compound 280-3 was synthesized according to Example 13.

[0690] 1. Synthesis of 3-1-21

[0691] 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. 280-3 (330 mg, 2.20 mmol) was then slowly added to the reaction system. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. 3-1-21 (89 mg, 15% yield) was obtained as an off-white solid by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 50%) and reverse phase preparative purification. MS Calcd.: 291.1 [M+H] + ;MS Found:291.2[M+H] + .

[0692] 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).

[0693] Example 61. Preparation of Compound 3-1-22 of the Present Invention

[0694] 1. Synthesis of compound 110-3

[0695] Compound 110-3 was synthesized according to Example 1.

[0696] 2. Synthesis of compound 3-1-22

[0697] 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 stirred at room temperature for two hours. 110-3 (492 mg, 3.0 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) and preparative liquid chromatography afforded 3-1-22 as an off-white solid (116.23 mg, yield: 13%). MS Calcd.: 291.1 [M+H] + ;MS Found:291.1[M+H] + .

[0698] 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).

[0699] Example 62: Preparation of Compound 3-1-23 of the Present Invention

[0700] 1. Synthesis of compound 110-3

[0701] Compound 110-3 was synthesized according to Example 1.

[0702] 2. Synthesis of compound 3-1-23

[0703] 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 allowed to react at room temperature for 2 hours. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) afforded compound 3-1-23 (289 mg, 0.97 mmol, 19% yield) as a white solid. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 23 N3OH + 298.1914; Found 298.1913.

[0704] 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.

[0705] Example 63. Preparation of Compound 3-1-24 of the Present Invention

[0706] 1. Synthesis of Compound 02-2

[0707] 02-1 (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 portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 h. Upon completion, the reaction was quenched by the addition of 3 mL of 15% NaOH solution, followed by the dropwise addition of 3 mL of water, and then 3 mL of 15% NaOH solution. The mixture was filtered through Celite and anhydrous Na2SO4, and concentrated under reduced pressure to afford compound 02-2 (3.74 g, 92% yield) as a yellow oil.

[0708] 2. Synthesis of Compound 02-3

[0709] 02-2 (270 mg, 2.0 mmol) was dissolved in Toluene (12 mL), and Triphosgene (297 mg, 1.0 mmol) was added. After the addition, the mixture was refluxed at 120°C for 4 h, and the toluene was dried by rotary evaporation. The obtained yellow oily crude product 02-3 was used directly in the next step.

[0710] 3. Synthesis of Compound 110-3

[0711] Compound 110-3 was synthesized according to Example 1.

[0712] 4. Synthesis of compound 3-1-24

[0713] 110-3 (164 mg, 1.0 mmol) and 02-3 (161 mg, 1.0 mmol) were dissolved in DCM (6.0 mL) and the mixture was brought to room temperature for 1 h. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) afforded compound 3-1-24 (50 mg, 15% yield) as a yellow solid. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 27 N3OH + 326.2227; Found 326.2229.

[0714] 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).

[0715] Example 64. Preparation of Compound 3-1-25 of the Present Invention

[0716] 1. Synthesis of compound 110-3

[0717] Compound 110-3 was synthesized according to Example 1.

[0718] 2. Synthesis of compound 110-3-2

[0719] 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 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was diluted with DCM. The mixture was washed twice with 20% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 110-3-2 (1.06 g, 65% yield) as a light yellow solid.

[0720] 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).

[0721] 3. Synthesis of compound 3-1-25

[0722] 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) afforded compound 3-1-25 (151 mg, 30% yield) as a white solid. HRMS (ESI-TOF) m / z: [M+H]+Calcd for C 15 H 22 N5O + 288.1819; Found 288.1824.

[0723] 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).

[0724] Example 65. Preparation of Compound 3-1-26 of the Present Invention

[0725] 1. Synthesis of compound 110-3-2

[0726] Compound 110-3-2 was synthesized according to Example 59.

[0727] 2. Synthesis of compound 3-1-26

[0728] 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 mixture was reacted at 50°C for 4 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) afforded the compound as a white solid (300 mg, 50% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 24 N5O + 302.1975; Found 302.1977.

[0729] 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).

[0730] Example 66. Preparation of Compound 3-2-1 of the Present Invention

[0731] 1. Synthesis of compound 110-3

[0732] Compound 110-3 was synthesized according to Example 1.

[0733] 2. Synthesis of compound 3-2-1

[0734] 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 added to the reaction system and stirred at room temperature for two hours. 110-3 (790 mg, 4.82 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to afford 3-2-1 (550 mg, yield: 37%) as a pale yellow solid. MS Calcd.: 321.1 [M+H] + ;MS Found:321.4[M+H] + .

[0735] 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).

[0736] Example 67. Preparation of Compound 3-2-2 of the Present Invention

[0737] 1. Synthesis of compound 110-3

[0738] Compound 110-3 was synthesized according to Example 1.

[0739] 2. Synthesis of compound 3-2-2

[0740] 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 added to the reaction system and stirred at room temperature for two hours. 110-3 (720 mg, 4.39 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to afford 3-2-2 (405 mg, yield: 29%) as a pale yellow solid. MS Calcd.: 320.1 [M+H] + ;MS Found:320.4[M+H] + .

[0741] 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).

[0742] Example 68. Preparation of Compound 3-2-3 of the Present Invention

[0743] 1. Synthesis of compound 110-3

[0744] Compound 110-3 was synthesized according to Example 1.

[0745] 2. Synthesis of compound INT-1

[0746] 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. The mixture was allowed to react at room temperature for 1 hour. DMAP (37 mg, 0.3 mmol) and Boc2O (2.3 mL, 10 mmol) were then added at 0°C, and the mixture was allowed to react 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 purified by column chromatography (PE / EtOAc = 40:1) to afford INT-1 (824 mg, 67% yield) as a yellow oil.

[0747] 2. Synthesis of compound 3-2-3

[0748] INT1 (237 mg, 1.15 mmol) and SM-7 (174 mg, 1.15 mmol) were dissolved in toluene (3 mL) and allowed to react overnight at room temperature. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) afforded compound 3-2-3 (210 mg, 57% yield) as a yellow oil. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 20 N4S2H + 321.1203; Found 321.1207.

[0749] 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).

[0750] Example 69. Preparation of Compound 3-2-4 of the Present Invention

[0751] 1. Synthesis of compound SM-17

[0752] SM-16 (1.77 mL, 20 mmol) was dissolved in EtOH (40 mL). CS2 (3.61 mL, 60 mmol) and triethylamine (2.78 mL, 20 mmol) were added at room temperature and allowed to react for 1 h. DMAP (73 mg, 0.6 mmol) and Boc2O (4.6 mL, 20 mmol) were then added at 0°C. The mixture was then allowed to react overnight at room temperature. After the reaction was complete, the solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 40:1) to afford SM-17 (2.35 g, 85% yield) as a yellow oil.

[0753] 2. Synthesis of Compound 110-3

[0754] Compound 110-3 was synthesized according to Example 1.

[0755] 3. Synthesis of compound 3-2-4

[0756] 110-3 (247 mg, 1.5 mmol) and SM-17 (209 mg, 1.5 mmol) were dissolved in Toluene (4.5 mL) and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) afforded compound 3-2-4 (342 mg, 75% yield) as a white solid. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N3OSH + 304.1479; Found 304.1471.

[0757] 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).

[0758] Example 70. Preparation of Compound 3-2-5 of the Present Invention

[0759] 1. Synthesis of compound INT1

[0760] Compound INT1 was synthesized according to Example 63.

[0761] 2. Synthesis of compound 3-2-5

[0762] INT-1 (309 mg, 1.5 mmol) and SM-18 (200 mg, 1.5 mmol) were dissolved in Toluene (4.5 mL) and the mixture was allowed to react at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 3:1) afforded compound 3-2-5 (170 mg, 40% yield) as a white solid. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N3OSH + 304.1479; Found 304.1473.

[0763] 1H 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).

[0764] Example 71. Preparation of Compound 3-2-6 of the Present Invention

[0765] 1. Synthesis of compound INT-1

[0766] Compound INT1 was synthesized according to Example 63.

[0767] 2. Synthesis of compound 3-2-6

[0768] 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. After stirring at room temperature for 2 hours, 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 obtain 3-2-6 as a white solid (287 mg, 95% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 22 N3OS + 304.1479; Found 304.1512.

[0769] 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).

[0770] Example 72. Preparation of Compound 3-2-7 of the Present Invention

[0771] 1. Synthesis of compound INT-1

[0772] Compound INT-1 was synthesized according to Example 63.

[0773] 2. Synthesis of compound 3-2-7

[0774] 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. After stirring at room temperature for 2 hours, INT-1 (206 mg, 1.0 mmol) was added. The reaction was continued with stirring 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 obtain 3-2-7 (287 mg, 95% yield) as a white solid. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 16 H 21 N3NaOS + 326.1298; Found 326.1308.

[0775] 1 H 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 .82(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.

[0776] Example 73. Preparation of Compound 3-2-8 of the Present Invention

[0777] 1. Synthesis of compound 110-3

[0778] Compound 110-3 was synthesized according to Example 1.

[0779] 2. Synthesis of compound INT10

[0780] 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. The mixture was allowed to react at room temperature for 1 hour. DMAP (22 mg, 0.18 mmol) and Boc2O (1.38 mL, 6 mmol) were then added at 0°C, and the mixture was allowed to react 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 purified by column chromatography (PE / EtOAc = 40:1) to afford INT-10 (778 mg, 63% yield) as a yellow oil.

[0781] 3. Synthesis of compound 3-2-8

[0782] 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 mixture was reacted at room temperature for 4 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) afforded compound 3-2-8 as a white solid (150 mg, 25% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N4OS + 305.1431; Found 305.1430.

[0783] 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.26 (s, 6H), 7.14 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 7.6 Hz, 2H), 6.84 (s, 1H), 6.16 (d, J = 1.7 Hz, 1H), 4.99 (d, J = 5.5 Hz, 2H), 4.31 (s, 2H), 2.66 (s, 6H), 2.33 (s, 3H). Example 74. Preparation of Compound 3-2-9 of the Present Invention

[0784] 1. Synthesis of compound 110-3

[0785] Compound 110-3 was synthesized according to Example 1.

[0786] 2. Synthesis of 3-2-9

[0787] 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 stirred at room temperature for two hours. 110-3 (506 mg, 3.09 mmol) was then added to the system and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol: 95:5] and then purified by preparative liquid chromatography to afford 3-2-9 as an off-white solid (105.25 mg, 11% yield). MS Calcd.: 304.2 [M+H] + ;MS Found:304.3[M+H] + .

[0788] 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).

[0789] Example 75. Preparation of Compound 3-2-10 of the Present Invention

[0790] 1. Synthesis of compound 3-2-9

[0791] Compound 3-2-9 was synthesized with reference to Example 74.

[0792] 2. Synthesis of compound INT-11

[0793] 3-2-9 (350 mg, 1.16 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (20 mL). Triethylamine (351 mg, 3.40 mmol), DMAP (15 mg, 0.12 mmol), and (Boc)2O (506 mg, 2.32 mmol) were then added sequentially to the system and stirred at 70°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure 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] + .

[0794] 3. Synthesis of compound INT-12

[0795] INT-11 (403 mg, 1.0 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (10 mL). Methyl iodide (213 mg, 1.5 mmol) was then added. The tube was sealed and stirred at 40°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1 to 2:1)] afforded INT-12 (400 mg, yield: 95%) as a light yellow solid. MS Calcd.: 417.2 [M+H] + ;MS Found:417.8[M+H] + .

[0796] 4. Synthesis of compound 3-2-10

[0797] INT-12 (400 mg, 0.96 mmol) was added to a sealed tube and dissolved in acetonitrile (10 mL). Ammonia (5 mL) was then added and stirred at 80°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] afforded an off-white solid 3-2-10 (106.86 mg, yield: 39%). MS Calcd.: 287.2 [M+H] + ;MS Found:287.3[M+H] + .

[0798] 1 H NMR (400MHz, CD3OD) δ: 7.21 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.01 (s, 2H), 6.96 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 4.35 (s, 2H), 2.61 (s, 6H), 2.32 (s, 3H).

[0799] Example 76. Preparation of Compound 3-2-11 of the Present Invention (P3-2-9-2)

[0800] 1. Synthesis of compound T7-4

[0801] Compound T7-4 was synthesized according to Example 53.

[0802] 2. Synthesis of compound T7-6

[0803] To a solution of T7-4 (1 g, 5.2 mmol) and DIEA (1.7 mL, 10.4 mmol) in dichloromethane (10 mL) was slowly added thiophosgene (0.44 mL, 5.7 mmol) at 0°C and stirred at room temperature for two hours. After the reaction was complete, the solvent was removed under reduced pressure to afford T7-6 (1.2 g, 98% yield).

[0804] 3. Synthesis of compound 3-2-11

[0805] To a tetrahydrofuran solution (10 mL) containing T7-6 (1.2 g, 5.1 mmol) was added SM-1 (1.16 g, 10.2 mmol) and DIEA (2 mL). 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. Column chromatography purification afforded 3-2-11 as a white solid (331 mg, 19% yield). LCMS: m / z calculated for [M+H] + 348.5,found 348.1.

[0806] 1 H NMR (400 MHz, 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).

[0807] Example 77. Preparation of Compound 3-2-12 of the Present Invention

[0808] 1. Synthesis of A3-2

[0809] Potassium nitrate (5.6 g, 55.3 mmol) was added to a sulfuric acid solution (10 mL) containing compound A3-1 (10 g, 50.2 mmol) at 0°C and stirred for 30 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure, 200 mL of water was added, and extraction was performed with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to afford A3-2 (4 g, 33% yield).

[0810] 2. Synthesis of A3-3

[0811] 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) at 0°C and stirred for 2 hours. After the reaction was complete, the mixture 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 yield A3-3 (3.5 g, 99% yield). m / z calculated for [M+H] + 151.1,found 151.1.

[0812] 3. Synthesis of A3-4

[0813] To a methanol solution (35 mL) containing compound A3-3 (3.5 g, 16.35 mmol) was added acetic acid (0.94 mL, 16.35 mmol), paraformaldehyde (8.2 g, 81.74 mmol), and sodium borohydride (3.09 g, 81.74 mmol) at 0°C and stirred for 16 hours. After completion, the reaction was concentrated under reduced pressure, 200 mL of water was added, and extraction was performed with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to yield a yellow oil, A3-4 (3.5 g, 88% yield). m / z calculated for [M+H] + 224.2,found 224.0.

[0814] 4. Synthesis of A3-5

[0815] Under nitrogen, 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) and stirred at 150°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, 200 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 afford A3-5 as a yellow oil (2.7 g, 99% yield). m / z calculated for [M+H] + 189.3,found 189.1.

[0816] 5. Synthesis of A3-6

[0817] To a tetrahydrofuran solution (10 mL) containing compound A3-5 (1.7 g, 9.03 mmol), lithium aluminum tetrahydride (14.45 mL) was slowly added and 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 extraction was performed with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to yield a yellow oil, A3-6 (1.0 g, 58% yield). m / z calculated for [M+H] + 193.3,found 193.1.

[0818] 6. Synthesis of A3-7

[0819] To a dichloromethane solution (10 mL) containing compound A3-6 (500 mg, 2.60 mmol) was added DIEA (1008.16 mg, 7.80 mmol) and thiophosgene (358.7 mg, 3.12 mmol), and stirred for half an hour. After the reaction was complete, the mixture was concentrated under reduced pressure to afford a black oil, A3-7 (0.50 g, 82% yield). m / z calculated for [M+H] + 235.4,found 235.1.

[0820] 7. Synthesis of 3-2-12

[0821] To a tetrahydrofuran solution (10 mL) containing compound A3-7 (500 mg, 2.13 mmol) was added DIEA (827.25 mg, 6.40 mmol) and thiophen-2-ylmethanamine (289.75 mg, 2.56 mmol). The mixture was stirred at room temperature for half an hour. After the reaction was complete, the mixture was concentrated under reduced pressure to afford 3-2-12 as a white solid (213 g, 28% yield). m / z calculated for [M+H] + 348.54,found 348.1.

[0822] 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).

[0823] Example 78. Preparation of Compound 3-2-13 of the Present Invention

[0824] 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 stirred at room temperature for two hours. SM-5 (226 mg, 2.0 mmol) was then added to the system and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. 3-2-13 (155 mg, 27% yield) 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, 27% yield). MS Calcd.: 290.1 ​​[M+H] + ;MS Found:290.4[M+H] + .

[0825] 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=8.8Hz,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).

[0826] Example 79. Preparation of Compound 3-2-14 of the Present Invention

[0827] 1. Synthesis of INT-3

[0828] INT-2 (3.3 g, 20 mmol) was dissolved in DMF (80 mL), potassium carbonate (6.07 g, 44 mmol) was added, and the mixture was stirred at 70°C. The reaction was allowed to react overnight, cooled to room temperature, diluted with water, extracted with ethyl acetate, and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated at room temperature, and purified by silica gel column chromatography to obtain INT-3 (2.5 g, 70% yield) as a yellow oil.

[0829] 2. Synthesis of INT-4

[0830] Dissolve INT-3 (2.5 g, 14 mmol) in methanol (20 mL) and add Pd / C (360 mg). After purging with argon, the atmosphere was replaced with hydrogen and stirred overnight under a hydrogen balloon. The reaction mixture was filtered through Celite, washed with methanol, and concentrated to afford INT-4 (2.09 g, crude product) as a red oil.

[0831] 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).

[0832] 3. Synthesis of INT-5

[0833] 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. The mixture was allowed to react at room temperature for 1 hour. DMAP (18 mg, 0.15 mmol) and Boc2O (1.2 mL, 5 mmol) were then added at 0°C, and the mixture was allowed to react 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 purified by column chromatography (PE / EtOAc = 40:1) to afford INT-5 (800 mg, 84% yield) as a yellow oil.

[0834] 4. Synthesis of 3-2-14

[0835] INT-5 (288 mg, 1.5 mmol) and SM-4 (150 mg, 1.5 mmol) were dissolved in methanol (5 mL) and allowed to react overnight at room temperature. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) afforded compound 3-2-14 (260 mg, 64% yield) as a yellow oil. HRMS (ESI-TOF) m / z: [M+Na]+ Calcd for C 14 H 18 N3S + 292.0937; Found 292.0937

[0836] 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=7.4Hz,1H),2.71(s,6H),2.32(s,3H).

[0837] Example 80. Preparation of Compound 3-2-15 of the Present Invention

[0838] 1. Synthesis of SM-27

[0839] 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 obtain compound SM-27 (400 mg, 80% yield) as a black oil.

[0840] 2. Synthesis of SM-28

[0841] To a solution of compound SM-27 (400 mg, 4.034 mmol) in THF (15 mL) was added CSCl (463.82 mg, 4.034 mmol) at 0°C, and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to afford compound SM-28 (380 mg, 67% yield) as a yellow oil.

[0842] 3. Synthesis of Compound 110-3

[0843] Compound 110-3 was synthesized according to Example 1.

[0844] 4. Synthesis of 3-2-15

[0845] Compound SM-28 (601.8 mg, 4.26 mmol) and DIEA (1.1 g, 8.52 mmol) were added to a solution of compound 110-3 (500 mg, 1.728 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at 50°C for 3 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate (50 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was purified by silica gel column chromatography to afford compound 3-2-15 (170.8 mg, 13.12% yield) as a light orange solid. MS Calcd.: 360.0 [M+H] + ;MS Found:360.0[M+H] + .

[0846] 1 H NMR (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).

[0847] Example 81. Preparation of Compound 3-2-16 of the Present Invention

[0848] 1. Synthesis of compound INT-6

[0849] SM-19 (0.75 mL, 5.0 mmol) was placed in 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 minutes, then brought 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 spun down to dryness. Purification by silica gel column chromatography (DCM) afforded INT-6 as a colorless oil (1.26 g, 87% yield).

[0850] 2. Synthesis of compound INT-7

[0851] Triphenylphosphine (8.61 g, 30 mmol) was weighed into a 100 mL flask under argon. Tetrahydrofuran (12 mL) and diisopropyl azodicarboxylate (DIAD) (7.2 mL, 36.0 mmol) were added at 0°C. A white solid quickly formed. After stirring at 0°C for 30 min, methanol (1.2 mL, 30.0 mmol) and a tetrahydrofuran solution (12 mL) of SM-30 (8.61 g, 30.0 mmol) were added. After stirring at 0°C for 2 h, the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (PE / EtOAc = 10:1) to afford SM-31 as a colorless oil (5.01 g, 71% yield).

[0852] SM-31 (5.01 g, 16.6 mmol) was dissolved in dichloromethane (17 mL). Trifluoroacetic acid (25.0 mL, 332.0 mmol, 20.0 equiv) was added at 0°C and stirred overnight. After completion, the reaction was quenched with ice-cold water at 0°C. The pH was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (PE / EtOAc = 5:1) to afford INT-7 (729 mg, 29% yield) as a pale yellow oil.

[0853] 3. Synthesis of compound INT8

[0854] INT-6 (843 mg, 3.0 mmol) was weighed into a 100 mL flask, and hexafluoroisopropanol (30 mL), 2,3-dichloro-5,6-dicyanobenzoquinone (1.021 g, 4.5 mmol), and INT-7 (905 mg, 4.5 mmol) were added. The mixture was stirred at room temperature under argon. After the reaction was complete, sodium cyanoborohydride (900 mg, 15.0 mmol) was added and allowed to react at room temperature. After completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (DCM) to afford INT-8 as a light yellow oil (706 mg, 75% yield).

[0855] 1 H 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).

[0856] 4. Synthesis of compound INT-9

[0857] INT-8 (706 mg, 2.2 mmol) was weighed into a 10 mL test tube, and methanol (3.0 mL) and Pd / C (220 mg) were added. The mixture was purged with hydrogen and stirred at room temperature. After the reaction was complete, the mixture was filtered through celite, dried under reduced pressure, and purified by silica gel column chromatography to obtain a light yellow solid INT-9 (390 mg, 99% yield).

[0858] 5. Synthesis of compound SM-28

[0859] Compound SM-28 was synthesized according to Example 74.

[0860] 6. Synthesis of compound 3-2-16

[0861] INT-9 (178 mg, 1.0 mmol) and SM-28 (141 mg, 1.0 mmol) were dissolved in toluene (2 mL) and allowed to react at room temperature for 2 hours. After the reaction was complete, column chromatography (PE / EtOAc = 5:1) afforded compound 3-2-16 (188 mg, 59% yield) as a yellow oil. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 21 N3S2H + 320.1250; Found 320.1248.

[0862] 1 H 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).

[0863] Example 82. Preparation of Compound 3-2-17 of the Present Invention

[0864] 1. Synthesis of compound INT-13

[0865] 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 hour, then brought to 0°C, and DMAP (16 mg, 0.13 mmol) and Boc2O (960 mg, 4.4 mmol) were added. The mixture was allowed to react at room temperature overnight. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and filtered through a column to yield 260 mg of INT-13, a 38% yield.

[0866] 2. Synthesis of Compound 217-2

[0867] Compound 217-2 was synthesized according to Example 17.

[0868] 3. Synthesis of compound 3-2-17

[0869] Dissolve 217-2 (290 mg, 1.7 mmol) and INT-13 (260 mg, 1.7 mmol) in 5.0 ml of toluene and stir for 2 hours. Monitor the reaction with a microplate reader. After completion, spin dry the mixture and apply it directly to a column to obtain 390 mg of 3-2-17, with a yield of 70%. MS (ESI) m / z: [M+H] + Calcd for:326.1; Found:326.1.

[0870] 1 H 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.

[0871] Example 83. Preparation of Compound 3-2-18 of the Present Invention

[0872] 1. Synthesis of 280-3

[0873] Compound 280-3 was synthesized according to Example 13.

[0874] 2. Synthesis of INT-14

[0875] 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 brought 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 allowed to react at room temperature overnight. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and filtered through a column chromatography column to obtain 340 mg of INT-14 (53% yield).

[0876] 3. Synthesis of 3-2-18

[0877] Dissolve INT-14 (100 mg, 0.52 mmol) and SM-27 (87 mg, 0.62 mmol) in 4 ml of dichloromethane, add triethylamine (108 μL, 0.78 mmol), and stir at room temperature. After the reaction is complete, spin dry the mixture and directly pass it through a column to obtain 3-2-1848 mg, with a yield of 31%. MS (ESI) m / z: [M+Na] + Calcd for:292.1; Found:282.9.

[0878] 1 H 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).

[0879] Example 84. Preparation of Compound 3-2-19 of the Present Invention

[0880] 1. Synthesis of compound INT-10

[0881] Compound 1NT-10 was synthesized according to Example 73.

[0882] 2. Synthesis of compound 3-2-19

[0883] 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 mixture was reacted at room temperature for 16 h. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) afforded compound 3-2-19 as a white solid (171 mg, 33% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H21 N4OS + 307.1046; Found 307.1048.

[0884] 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).

[0885] Example 85. Preparation of Compound 3-2-20 of the Present Invention

[0886] 1. Synthesis of compound 110-3

[0887] Compound 110-3 was synthesized according to Example 1.

[0888] 2. Synthesis of compound 3-2-20

[0889] Compound 110-3 (164 mg, 1.0 mmol) and SM-34 (149 mg, 1.0 mmol) were dissolved in toluene (3.0 mL) and allowed to react at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) afforded compound 3-2-20 as a white solid (220 mg, 59% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3S + 314.1686; Found 314.1684.

[0890] 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).

[0891] Example 86. Preparation of Compound 3-2-21 of the Present Invention

[0892] 1. Synthesis of 140-3

[0893] Compound 140-3 was synthesized according to Example 18.

[0894] 2. Synthesis of 3-2-21

[0895] Compound 140-3 (164 mg, 1.0 mmol) and compound B (149 mg, 1.0 mmol) were dissolved in toluene (3.0 mL) and allowed to react at room temperature for 2 h. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) afforded compound 3-2-21 as a yellow oil (203 mg, 65% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3S + 314.1686; Found 314.1689.

[0896] 1 H 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).

[0897] Example 87. Preparation of Compound 3-2-22 of the Present Invention

[0898] 1. Synthesis of compound INT-10

[0899] Compound 1NT-10 was synthesized according to Example 73.

[0900] 2. Synthesis of compound 3-2-22

[0901] 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) afforded 3-2-22 as a white solid (171 mg, 32% yield). HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 16 H 23 N4OS + 340.1566; Found 340.1563.

[0902] 1H 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).

[0903] Example 88. Preparation of Compound 3-2-23 of the Present Invention

[0904] 1. Synthesis of INT-15

[0905] SM-35 (1.89 g, 10.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) were weighed into a 100 mL flask, and dimethylamine hydrochloride (1.64 g, 20.0 mmol) and DMSO 20 mL were added. The mixture was stirred at 70 ° C overnight. After the reaction was complete, it was cooled to room temperature and diluted with an appropriate amount of ethyl acetate. The DMSO was removed by extraction with water, dried over anhydrous sodium sulfate, and dried by spin drying. The product INT-15 (2.04 g, 95% yield) was obtained as a light yellow oil by purification by silica gel column chromatography (PE: DCM = 5:1).

[0906] 2. Synthesis of INT-16

[0907] The product INT-15 (2.04 g, 9.5 mmol) was dissolved in 24 mL of anhydrous ether, and lithium aluminum hydride (722 mg, 19 mmol) was slowly added several times 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. 3 mL of 15% sodium hydroxide solution and 3 mL of water were then added, followed by drying over anhydrous sodium sulfate, filtration, washing with ethyl acetate, and spin drying. The product C (1.96 g, 95% yield) was obtained as a light yellow oil after purification by silica gel column chromatography (DCM:MeOH = 20:1).

[0908] 3. Synthesis of compound INT-13

[0909] Compound INT-13 was synthesized according to Example 82.

[0910] 4. Synthesis of compound 3-2-23

[0911] INT-16 (240 mg, 1.1 mmol) was weighed into a 50 mL flask, toluene (2.5 mL) and INT-13 (155 mg, 1.0 mmol) were added, and the mixture was stirred at room temperature. After the reaction was complete, it was purified by silica gel column chromatography (PE / EtOAc = 5:1) to obtain 3-2-23 as a white solid: 363 mg, 97% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 19 F3N3S2 + 374.0967; Found 374.0996.

[0912] 1 H 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).

[0913] Example 89. Preparation of Compound 3-2-24 of the Present Invention

[0914] 1. Synthesis of INT-17

[0915] To a solution of 110-1 (1.35 g, 10 mmol) in DMSO (20 mL) was added morpholine (2.6 mL, 30 mmol) and potassium carbonate (4.14 g, 30 mmol). The mixture was heated to 70°C and allowed to react overnight. After the reaction was complete, the solution was diluted and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford INT-17 as a yellow oil, which was used directly in the next step.

[0916] 2. Synthesis of INT-18

[0917] 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 portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 h. After completion of the reaction, 3 mL of 15% NaOH solution was added to quench the reaction, followed by 3 mL of water and then 3 mL of 15% NaOH solution. The mixture was filtered through celite and anhydrous sodium sulfate, and concentrated under reduced pressure to afford INT-18 (332 mg, 64% yield) as a yellow oil.

[0918] 3. Synthesis of compound INT-13

[0919] Compound INT-13 was synthesized according to Example 82.

[0920] 4. Synthesis of 3-2-24

[0921] INT-18 (248 mg, 1.2 mmol, 1.2 equiv.) was dissolved in toluene (2 mL) and SM-13 (155 mg, 1.0 mmol) was added. After approximately 0.5 h at room temperature, the reaction was complete and then directly purified by column chromatography (DCM) to afford the product 3-2-24 as a white solid (220 mg, 61% yield). HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 18 H 23 N3NaOS2 + 384.1175; Found 384.1184.

[0922] 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).

[0923] Example 90. Preparation of Compound 3-2-25 of the Present Invention

[0924] 1. Synthesis of 3-2-14

[0925] Compound 3-2-1 was synthesized with reference to Example 61.

[0926] 2. Synthesis of 3-2-25

[0927] 3-2-1 (280 mg, 0.84 mmol) was added to a sealed tube and dissolved in acetonitrile (15 mL). Ammonia (5 mL) was then added and the tube was sealed and stirred at 80°C overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography [dichloromethane:methanol (100:1-5:1)] and preparative liquid chromatography to obtain an off-white solid 3-2-25 (162.76 mg, 64%). ESI [M+H] + =304.4.

[0928] 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).

[0929] Example 91. Preparation of Compound 3-2-26 of the Present Invention

[0930] 1. Synthesis of 3-2-9

[0931] Compound 3-2-9 was synthesized with reference to Example 74.

[0932] 2. Synthesis of 2-7-5

[0933] 3-2-9 (350 mg, 1.16 mmol) was added to a reaction flask and dissolved in THF (20 mL). Triethylamine (351 mg, 3.40 mmol), DMAP (15 mg, 0.12 mmol), and (Boc)2O (506 mg, 2.32 mmol) were then added sequentially to the system and stirred at 70°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] to obtain 2-7-5 (410 mg, 88% yield). MS Calcd.: 404.2 [M+H] + ;MS Found:404.2[M+H] + .

[0934] 3. Synthesis of 2-7-6

[0935] 2-7-5 (403 mg, 1.0 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (10 mL). Methyl iodide (213 mg, 1.5 mmol) was then added. The tube was sealed and stirred at 40°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1 to 2:1)] afforded 2-7-6 as a light yellow solid (400 mg, yield: 95%). MS Calcd.: 418.2 [M+H] + ;MS Found:417.8[M+H] + .

[0936] 3. Synthesis of 3-2-26

[0937] 2-7-6 (400 mg, 0.96 mmol) was added to a sealed tube and dissolved in acetonitrile (10 mL). Ammonia (5 mL) was then added and stirred at 80°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] and SFC afforded an off-white solid 3-2-26 (106.86 mg, yield: 39%). ESI MS Calcd.: 287.2 [M+H] + ;MS Found:287.3[M+H] + .

[0938] 1 H NMR (400MHz, CD3OD) δ: 7.21 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.01 (s, 2H), 6.96 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 4.35 (s, 2H), 2.61 (s, 6H), 2.32 (s, 3H).

[0939] Example 92. Preparation of Compound 3-2-27 of the Present Invention

[0940] 1. Synthesis of INT-19

[0941] SM-36 (2.26 g, 20 mmol) was dissolved in tetrahydrofuran (12 mL) and purged with Ar. BH3·THF (60 mL, 60 mmol) was added dropwise at 0°C and allowed to react at room temperature for 16 hours. The mixture was quenched with ethanol at 0°C and extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 3:1) to afford INT-19 (1.25 g, 63% yield) as a colorless oil.

[0942] 2. Synthesis of INT-21

[0943] 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). Triphenylphosphine (1.6 g, 6.3 mmol) was added, followed by the slow dropwise addition of DIAD (1.2 g, 6.3 mmol) at 0°C. The mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc = 20:1) to afford the compound as a colorless oil (1.11 g, 67% yield).

[0944] 3. Synthesis of Compound 110-3

[0945] Compound 110-3 was synthesized according to Example 1.

[0946] 4. Synthesis of INT-22

[0947] INT-21 (1.11 g, 2.8 mmol) and 110-3 (459 mg, 2.8 mmol) were dissolved in 1,4-dioxane (5 mL). Triethylamine (2.8 g, 28 mmol) was added and the mixture was reacted at 45°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc = 20:1) to afford the compound as a colorless oil (925 mg, 68% yield).

[0948] 5. Synthesis of 3-2-27

[0949] INT-22 (487 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), and a solution of hydrochloric acid in 1,4-dioxane (5 mL, 4.0 M) was added. The mixture was allowed to react at room temperature for 16 hours, resulting in the precipitation of a white solid. The mixture was filtered, washed with ethyl acetate, and recrystallized (MeOH / EA) to afford 3-2-27 as a white solid (82 mg, 25% yield). HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 15 H 22 N5ONa + 310.1635; Found 310.1638.

[0950] 1 H NMR (400MHz, Methanol-d4) δ8.39(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).

[0951] Example 93. Preparation of Compound 3-2-28 of the Present Invention

[0952] 1. Synthesis of compound INT-10

[0953] Compound INT-10 was synthesized according to Example 73.

[0954] 2. Synthesis of compound 3-2-28

[0955] INT-10 (180 mg, 1.1 mmol) was dissolved in toluene (2 mL), and SM-37 (206 mg, 1.0 mmol) was added. The reaction was allowed to proceed at room temperature for approximately 0.5 h. Upon completion, the mixture was concentrated under reduced pressure, and the resulting solid was recrystallized from PE:EtOAc to afford 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.

[0956] 1 H NMR (400MHz, CDCl3) δ7.78 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H),7.37–7.27(m,2H),7.16(d,J=7.7Hz,1H),7.09(s,1H),6.94(d,J=8.2 Hz,1H),6.86(s,1H),5.06(s,2H),4.35(s,2H),2.50(s,6H),2.30(s,3H).

[0957] Example 94. Preparation of Compound 3-2-29 of the Present Invention

[0958] SM-37 (509 mg, 3.2 mmol) was dissolved in diethyl ether (8 mL), and lithium aluminum tetrahydride (244 mg, 6.4 mmol) was slowly added portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, 3 mL of 15% NaOH solution was added to quench the reaction, followed by 3 mL of water and then 3 mL of 15% NaOH solution. The mixture was filtered through celite and anhydrous sodium sulfate, and concentrated under reduced pressure to afford INT-23 (347 mg, 66% yield) as a yellow oil.

[0959] 2. Synthesis of compound INT10

[0960] Compound 1NT-10 was synthesized according to Example 73.

[0961] 3. Synthesis of 3-2-29

[0962] INT-23 (309 mg, 1.9 mmol) was dissolved in toluene (2 mL), and thioisocyanate INT-10 (412 mg, 2.0 mmol) was added. After reacting at room temperature for approximately 0.5 hours, the reaction was concentrated under reduced pressure and the resulting solid was recrystallized to yield 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.

[0963] 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).

[0964] Example 95. Preparation of Compound 3-2-30 of the Present Invention

[0965] 1. Synthesis of 6-1-2

[0966] To the reaction flask, 6-1-1 (2.0 g, 10 mmol) and 4N dioxane hydrochloride solution (20 mL) were added sequentially and the reaction system was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a light yellow solid 6-1-2 (1.0 g, 74% yield).

[0967] 2. Synthesis of 6-1-3

[0968] 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 added to the reaction system and stirred at room temperature for two hours. 6-1-2 (675 mg, 5.0 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to afford 6-1-3 (800 mg, 58% yield) as a pale yellow solid. MS Calcd.: 278.1 [M+H]+ ;MS Found:278.4[M+H] + ..

[0969] 3. Synthesis of 6-1-4

[0970] 6-1-3 (800 mg, 2.89 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (15 mL). Methyl iodide (616 mg, 4.34 mmol) was then added to the reaction system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) to obtain a light yellow semi-solid 6-1-4 (400 mg, 48% yield). MS Calcd.: 292.1 [M+H] + ;MS Found:292.4[M+H] + ..

[0971] 4. Synthesis of 3-2-20

[0972] To a sealed reaction tube, 6-1-4 (400 mg, 1.37 mmol) was added and dissolved in acetonitrile (10 mL). 25% aqueous ammonia (932 mg, 13.7 mmol) was then added to the reaction system and stirred overnight at 80°C. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse phase preparative purification afforded 3-2-20 (130 mg, 33% yield) as a white solid. MS Calcd.: 261.1 [M+H] + ;MS Found:261.4[M+H] + .

[0973] 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).

[0974] Example 96. Preparation of Compound 3-2-31 of the Present Invention

[0975] 1. Synthesis of 6-2-2

[0976] 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 added to the reaction system and stirred at room temperature for two hours. 6-2-1 (945 mg, 5.0 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) to afford 6-2-2 (800 mg, 58% yield) as a pale yellow solid. MS Calcd.: 278.1 [M+H] + ;MS Found:287.4[M+H] + .

[0977] 2. Synthesis of 6-2-3

[0978] 6-2-2 (800 mg, 2.89 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (15 mL). Methyl iodide (616 mg, 4.34 mmol) was then added to the reaction system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) to afford a pale yellow semi-solid 6-2-3 (400 mg, 48% yield). MS Calcd.: 292.1 [M+H] + ;MS Found:292.4[M+H] + .

[0979] 3. Synthesis of 3-2-21

[0980] 6-2-3 (400 mg, 1.37 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (10 mL). 25% aqueous ammonia (932 mg, 13.7 mmol) was then added to the reaction system and stirred overnight at 80°C. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 5%) and reverse phase preparative purification afforded 3-2-21 (201.32 mg, 56% yield) as a white solid. MS Calcd.: 261.1 [M+H] + ;MS Found:261.4[M+H] + .

[0981] 1H 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).

[0982] Example 97. Preparation of Compound 3-2-32 of the Present Invention

[0983] 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 stirred at room temperature for 4 hours. SM-20 (408 mg, 3.0 mmol) was then added to the system and stirred at 45°C overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 3%) and preparative liquid chromatography afforded 3-2-32 as an off-white solid (131.88 mg, yield: 17.5%). MS Calcd.: 263.1 [M+H] + ;MS Found:263.2[M+H] + .

[0984] 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).

[0985] Example 98. Preparation of Compound 3-2-33 of the Present Invention

[0986] 1. Synthesis of 274-2

[0987] 274-1 (5.0 g, 30.3 mmol) was added to a 500 mL reaction flask and dissolved in alcohol (150 mL). Then, aqueous formaldehyde (24.0 g, 300.3 mmol), acetic acid (9.0 g, 151.5 mmol), and sodium cyanoborohydride (9.5 g, 151.5 mmol) were added in sequence and allowed to react at room temperature overnight. 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, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 274-2 (5.0 g, yield: 85%). MS Calcd.: 194.1 [M+H] + ;MS Found:194.4[M+H] + ..

[0988] 2. Synthesis of 274-3

[0989] To a reaction flask, 274-2 (5.0 g, 25.91 mmol) and THF (120 mL) were added. The atmosphere was replaced with a nitrogen balloon three times and cooled to 0°C in an ice bath. Lithium aluminum hydride (2.5N in THF, 20.7 mL, 51.8 mmol) was slowly added dropwise and stirred at room temperature overnight. After the reaction was complete, the system was cooled to 0°C and water (2 mL), 15% NaOH (2 mL), and water (6 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography (dichloromethane:methanol (20:1)) afforded 274-3 as a yellow oil (4.2 g, yield: 99%). MS Calcd.: 166.1 [M+H] + ;MS Found:166.3[M+H] + ..

[0990] 3. Synthesis of 274-4

[0991] 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 with nitrogen three times and stirred at 100°C overnight. After the reaction was complete, sodium hydroxide was added to the reaction mixture until the pH reached 13, and the mixture was stirred at 100°C for 0.5 hours under nitrogen. The reaction mixture was diluted with aqueous sodium hydroxide (1 M, 30 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow liquid 274-4 (0.60 g, yield: 36%). MS Calcd.: 182.1 [M+H] +;MS Found:182.3[M+H] + ..

[0992] 4. Synthesis of Compound 274-5

[0993] Dissolve 274-4 (0.30 g, 1.65 mmol) in tetrahydrofuran (15 mL) and add sodium hydride (60%, 0.10 g, 2.48 mmol). Replace the atmosphere with nitrogen three times and stir at room temperature for 0.5 hour. Add carbon disulfide (1.26 g, 16.55 mmol) and continue stirring at room temperature for 1 hour. The reaction mixture is dried to give crude compound 274-5 as a yellow solid.

[0994] 5. Synthesis of compound 3-2-33

[0995] 274-5 (0.50 g, 1.79 mmol) was dissolved in tetrahydrofuran (15 mL), and SM-50 (0.35 g, 1.97 mmol) was added. The atmosphere was replaced with nitrogen three times, and the reaction was stirred at room temperature overnight under a nitrogen atmosphere. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. Silica gel column chromatography of the crude product gave 3-2-33 (0.21 g, yield: 33%) as a yellow liquid. MS Calcd.: 354.1 [M+H] + ;MS Found:354.0[M+H] + .

[0996] 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).

[0997] Example 99. Preparation of Compound 3-2-34 of the Present Invention

[0998] 1. Synthesis of compound 274-4

[0999] Compound 274-4 was synthesized with reference to Example 98.

[1000] 4. Synthesis of 3-2-34

[1001] 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 stirred at room temperature for two hours. 274-4 (300 mg, 1.66 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (20:1)] and reverse synthesis to obtain 3-2-34 (221.27 mg, yield: 42%) as a white solid. MS Calcd.: 321.1 [M+H] + ;MS Found:321.4[M+H] + ..

[1002] 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).

[1003] Example 100. Preparation of Compound 3-2-35 of the Present Invention

[1004] 1. Synthesis of compound 274-3

[1005] Compound 274-3 was synthesized with reference to Example 99.

[1006] 2. Synthesis of compound 278-6-1

[1007] 274-3 (500 mg, 3.03 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (15 mL). Sodium hydroxide (118 mg, 3.94 mmol) was slowly added to the mixture and stirred at room temperature for half an hour. Carbon disulfide (2.3 g, 30.3 mmol) was dissolved in tetrahydrofuran (10 mL) and slowly added to the mixture. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain crude product 278-6-1, which was used directly in the next reaction without purification.

[1008] 3. Synthesis of compound 3-2-35

[1009] The crude product (700 mg, 2.66 mmol) obtained above 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 and stirred at room temperature overnight. After the reaction was complete, the reaction solution was slowly poured into ice water (2 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. Purification by forward column chromatography and preparative liquid chromatography gave 3-2-35 as a colorless oil (212.95 mg, yield: 24%). MS Calcd.: 338.1 [M+H] + ;MS Found:338.4[M+H] + ..

[1010] 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).

[1011] Example 101. Preparation of Compound 3-2-36 of the Present Invention

[1012] 1. Synthesis of compound 274-4

[1013] Compound 274-4 was synthesized with reference to Example 99.

[1014] 2. Synthesis of compound 3-2-26

[1015] 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 stirred at room temperature for two hours. 274-4 (278 mg, 1.54 mmol) was added to the system and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by reverse phase preparative chromatography to afford 3-2-26 as a pale yellow oil (155.48 mg, yield: 30%). MS Calcd.: 338.1 [M+H] + ;MS Found:338.1[M+H] + ..

[1016] 1H 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).

[1017] Example 102. Preparation of Compound 3-2-37 of the Present Invention

[1018] 1. Synthesis of INT-24

[1019] 19-1 (600 mg, 4.55 mmol) was added to a reaction flask and dissolved in methanol (25 mL). Then, aqueous formaldehyde (3.69 g, 45.5 mmol), acetic acid (1.37 g, 22.75 mmol), and sodium cyanoborohydride (1.43 g, 22.75 mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen atmosphere overnight. After completion of the reaction, water (40 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (40 mL) three times, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a residue. The residue was purified by column chromatography [petroleum ether:ethyl acetate (20:1-5:1)] to obtain 19-2 (560 mg, yield: 77%) as a yellow oil. MS Calcd.: 161.1 [M+H] + ;MS Found:161.4[M+H] + .

[1020] 2. Synthesis of INT-25

[1021] To a reaction flask, INT-24 (560 mg, 3.50 mmol) and tetrahydrofuran (15 mL) were added. The atmosphere was replaced three times with a nitrogen balloon and cooled to 0°C under a nitrogen atmosphere. Lithium aluminum tetrahydride (2.5N tetrahydrofuran solution, 7.0 mmol, 2.8 mL) was then added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was complete, the system was cooled to 0°C, and water (0.6 mL), 15% aqueous sodium hydroxide solution (0.6 mL), and water (1.8 mL) were slowly added. The mixture was stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by forward column chromatography [dichloromethane:methanol (100:1-20:1)] afforded INT-25 (300 mg, yield: 52%) as a yellow oil.

[1022] 3. Synthesis of SM-7

[1023] Compound SM-7 was synthesized according to Example 36.

[1024] 4. Synthesis of INT-25

[1025] 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 added to the mixture and stirred at room temperature for two hours. INT-25 (300 mg, 1.83 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (eluent: dichloromethane-methanol (100:1-20:1)) and reverse synthesis to afford 3-2-37 (170.6 mg, 31% yield) as a white solid.

[1026] 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).

[1027] Example 103. Preparation of Compound 3-2-38 of the Present Invention

[1028] 1. Synthesis of compound 110-3

[1029] Compound 110-3 was synthesized according to Example 1.

[1030] 2. Synthesis of INT-26

[1031] SM-39 (1.01 g, 5 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (1.05 mL, 7.5 mmol, 1.5 equiv) was added. 110-3 (820 mg, 5 mmol) was slowly added dropwise at -10°C. After complete addition, the reaction was continued at -10°C for 16 hours. After completion of the reaction, water was added to quench the reaction, followed by dilution with dichloromethane, washing twice with 20% aqueous sodium bicarbonate solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to afford INT-26 (1.06 g, 65% yield) as a pale yellow solid.

[1032] 3. Synthesis of 3-2-38

[1033] 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 purified by column chromatography (DCM / MeOH = 10:1) to obtain a crude product. This was then recrystallized from acetone to obtain a pale yellow solid. Further purification by reverse-phase column chromatography (MeCN / H2O = 50% for 30 min) afforded 3-2-38 as a white solid (70 mg, 3.5% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 14 H 20 N5O + 274.1662; Found 274.1667.

[1034] 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).

[1035] Example 104. Preparation of Compound 3-2-39 of the Present Invention

[1036] 1. Synthesis of compound INT-27

[1037] SM-41 (812 mg, 4.0 mmol) was dissolved in toluene (12 mL), and solid phosgene (594 mg, 2.0 mmol) was added. After the addition was complete, the mixture was moved to 120°C and refluxed for 4 hours. The toluene was then dried by rotary evaporation, and the resulting yellow oily crude product INT-27 was directly used in the next step.

[1038] 2. Synthesis of Compound 110-3

[1039] Compound 110-3 was synthesized according to Example 1.

[1040] 3. Synthesis of compound 3-2-39

[1041] 110-3 (656 mg, 4.0 mmol) and INT-27 (436 mg, 4.0 mmol) were dissolved in dichloromethane (6.0 mL) and allowed to react at room temperature for 1 hour. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) afforded compound 3-2-39 as a yellow oil: 152 mg, 14% yield. HRMS (ESI-TOF) m / z: [M+ Na] + Calcd for C 14 H 19 N5ONa + 296.1482; Found 296.1481.

[1042] 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).

[1043] Example 105. Preparation of Compound 3-2-40 of the Present Invention

[1044] 1. Synthesis of compound INT-28

[1045] 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 reaction mixture was heated to 70°C and allowed to react overnight. After the reaction was complete, the solution was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain INT-28 as a yellow oil.

[1046] 2. Synthesis of compound INT-29

[1047] INT-28 was dissolved in ether (20 mL), and lithium aluminum hydride (0.95 g, 25 mmol) was slowly added portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, 3 mL of 15% sodium hydroxide solution was added to quench the reaction, followed by 3 mL of water and then 3 mL of 15% sodium hydroxide solution. The mixture was filtered through celite and anhydrous sodium sulfate, and concentrated under reduced pressure to afford INT-29 (1.85 g, 85% yield) as a yellow oil.

[1048] 3. Synthesis of compound INT-30

[1049] SM-16 (4.84 g, 24 mmol) was dissolved in dichloromethane (60 mL). Triethylamine (8.4 mL, 60 mmol) was added at –10°C. SM-39 (1.8 mL, 20 mmol) was then 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 x 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 15:1) to afford INT-30 (1.77 g, 34% yield) as a white solid.

[1050] 4. Synthesis of compound 3-2-40

[1051] INT-29 (327 mg, 1.5 mmol) and INT-30 (393 mg, 1.5 mmol) were dissolved in acetonitrile (3.0 mL) and the reaction mixture was heated to 65°C for 3 hours. After the reaction was complete, column chromatography (PE / EtOAc = 2:1) afforded 324 mg of a yellow solid compound 3-2-40 in a 63% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 19 F3N3O2 + 342.1424; Found 342.1423.

[1052] 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=3.0Hz,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.

[1053] Example 106. Preparation of Compound 3-2-41 of the Present Invention

[1054] 1. Synthesis of compound INT-31

[1055] 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 portionwise. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EtOAc = 10:1) afforded INT-31 (156 mg, 1.1 mmol, 44% yield) as a colorless oil.

[1056] 2. Synthesis of Compound 110-3

[1057] Compound 110-3 was synthesized according to Example 1.

[1058] 3. Synthesis of compound 3-2-41

[1059] INT-31 (156 mg, 1.1 mmol) and 110-3 (198 mg, 1.21 mmol) were dissolved in toluene (2 mL) and stirred at room temperature for 3 hours to precipitate a white solid. After the reaction was complete, the mixture was filtered and the filter cake washed with PE:EA = 10:1 to obtain a white solid product. The white solid was dissolved in chloroform and filtered through Celite. The filtrate was concentrated to obtain the 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.

[1060] 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).

[1061] Example 107. Preparation of Compound 3-2-42 of the Present Invention

[1062] 1. Synthesis of compound INT-10

[1063] Compound INT-10 was synthesized according to Example 73.

[1064] 2. Synthesis of compound 3-2-42

[1065] Pyrazole SM-44 (101 mg, 0.81 mmol) was added to 6 ml of dichloromethane, followed by INT-10 (200 mg, 0.97 mmol), and stirred at room temperature. After the reaction was complete, the mixture was dried and passed through a column to obtain 180 mg of compound 3-2-42 in a 71% yield. MS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5S + :332.1;Found:332.1.

[1066] 1 H 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).

[1067] Example 108. Preparation of Compound 3-2-43 of the Present Invention

[1068] 1. Synthesis of compound 3-2-42

[1069] Compound 3-2-42 was synthesized according to Example 107.

[1070] 2. Synthesis of compound 3-2-42-A

[1071] To a tetrahydrofuran solution containing 3-2-42 (450 mg, 1.36 mmol) was added iodomethane (1.10 mL, 13.58 mmol) and 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 used directly in the next reaction.

[1072] 3. Synthesis of compound 3-2-43

[1073] Aqueous ammonia (8 mL) was added to a solution of 3-2-42-A (480 mg, 1.39 mmol) in tetrahydrofuran (5 mL), 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 purified by column chromatography to afford 3-2-43 as a white solid (60.8 mg, 14% yield). m / z calculated for [M+H] + 315.1,found 315.1.

[1074] 1 H 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).

[1075] Example 109. Preparation of Compound 3-2-44 of the Present Invention

[1076] 1. Synthesis of 140-3

[1077] Compound 140-3 was synthesized according to Example 18.

[1078] 2. Synthesis of INT-33

[1079] 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 hour, then brought to 0°C, and DMAP (74 mg, 0.6 mmol) and Boc2O (1.44 g, 6.6 mmol) were added. The mixture was allowed to react at room temperature overnight. After the reaction was complete, the mixture was checked by spotting. Water was added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and filtered through a column chromatography column to obtain 655 mg of the target compound INT-33 in a 53% yield.

[1080] 3. Synthesis of compound 3-2-51

[1081] Pyrazole 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 at room temperature overnight. After the reaction was complete, the mixture was dried and passed through a column to obtain 185 mg of the target compound 3-2-51 in a 71% yield. MS (ESI) m / z: [M+H] + Calcd for C 16 H 24 N5S + :318.1;Found:318.1.

[1082] 4. Synthesis of compound 3-2-51-A

[1083] To a solution of 3-2-51 (500 mg, 1.58 mmol) in acetonitrile (10 mL) was added potassium iodide (1.28 mL, 15.75 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 give crude 3-2-51-A which was used directly in the next step.

[1084] 5. Synthesis of compound 3-2-44

[1085] Aqueous ammonia (10 mL) was added to a solution of 3-2-51-A (500 mg, 1.51 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at 80°C for 14 hours. After the reaction was complete, the solvent was removed under reduced pressure and purified by preparative chromatography to give 3-2-44 as a white solid (163 mg, 36% yield). m / z calculated for [M+H] + 301.4,found 301.1.

[1086] 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).

[1087] Example 110. Preparation of Compound 3-2-45 of the Present Invention

[1088] 1. Synthesis of INT-33

[1089] Compound INT-33 was synthesized according to Example 109.

[1090] 2. Synthesis of 3-2-50

[1091] Pyrazole SM-44 (80 mg, 0.64 mmol) was added to 5 mL of dichloromethane, followed by INT-33 (160 mg, 0.78 mmol), and stirred at room temperature. After the reaction was complete, the reaction mixture was dried and passed through a column to obtain 152 mg of the target compound 3-2-50 in a 75% yield. HRMS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5S + :332.2;Found:332.2.

[1092] 3. Synthesis of 3-2-50-A

[1093] To a solution of 3-2-50 (700 mg, 2.11 mmol) in acetonitrile (10 mL) was added potassium iodide (1.71 mL, 21.12 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 give crude 3-2-50-A, which was used directly in the next step.

[1094] 4. Synthesis of 3-2-45

[1095] Aqueous ammonia (10 mL) was added to a solution of 3-2-50-A (700 mg, 2.03 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at 80°C for 14 hours. After the reaction was complete, the solvent was removed under reduced pressure and purified by preparative chromatography to give 3-2-45 as a white solid (130 mg, 20% yield). m / z calculated for [M+H] + 315.4,found 315.1.

[1096] 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).

[1097] Example 111. Preparation of Compound 3-2-46 of the Present Invention

[1098] 1. Synthesis of compound 3-2-22

[1099] Compound 3-2-22 was synthesized according to Example 87.

[1100] 2. Synthesis of compound 3-2-22-A

[1101] To a solution of 3-2-22 (450 mg, 1.42 mmol) in tetrahydrofuran (10 mL) was added potassium iodide (1.15 mL, 14.2 mmol) and stirred at 40°C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure to give crude 3-2-22-A, which was used directly in the next step.

[1102] 3. Synthesis of compound 3-2-46

[1103] Aqueous ammonia (8 mL) was added to a solution of 3-2-22-A (450 mg, 1.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at 80°C for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure and purified by preparative chromatography to give 3-2-45 as a white solid (82.7 mg, 21% yield). m / z calculated for [M+H] + 301.1,found 301.1.

[1104] 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).

[1105] Example 112. Preparation of Compound 3-2-47 of the Present Invention

[1106] 1. Synthesis of Compound 140-3

[1107] Compound 140-3 was synthesized according to Example 18.

[1108] 2. Synthesis of compound INT-32

[1109] Benzylamine 110-3 (1.0 g, 6.0 mmol) was dissolved in dichloromethane and placed at 0°C. Carbonyldiimidazole SM-45 (1.46 g, 9 mmol) was added and stirred at 0°C for 4 hours. The reaction mixture was spin-dried and filtered through a column to obtain 990 mg of the desired product INT-32 in a 64% yield.

[1110] 3. Synthesis of compound 3-2-47

[1111] Pyrazole 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 at room temperature overnight. After the reaction was complete, the mixture was dried and passed through a column to obtain 154 mg of the target compound 3-2-47 in an 82% yield. MS (ESI) m / z: [M+H] + Calcd for C 16 H 24 N5O:302.1;Found:302.0.

[1112] 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).

[1113] Example 113. Preparation of Compound 3-2-48 of the Present Invention

[1114] 1. Synthesis of INT-32

[1115] Compound INT-32 was synthesized according to Example 112.

[1116] 2. Synthesis of 3-2-48

[1117] Pyrazole 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 at room temperature overnight. After the reaction was complete, the mixture was dried and passed through a column to obtain 150 mg of compound 3-2-48 in an 82% yield. MS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5O:316.2;Found:316.1.

[1118] 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).

[1119] Example 114. Preparation of Compound 3-2-49 of the Present Invention

[1120] 1. Synthesis of SM-27

[1121] Compound SM-27 was synthesized according to Example 80.

[1122] 2. Synthesis of SM-27-A

[1123] To a solution of SM-27 (180 mg, 2.01 mmol) in tetrahydrofuran (5 mL) was added DIEA (1042.85 mg, 8.07 mmol) and thiophosgene (463.82 mg, 4.03 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure to afford a brown oil, SM-27-A, which was used directly in the next step.

[1124] 3. Synthesis of T7-4

[1125] Compound T7-4 was synthesized according to Example 53.

[1126] 4. Synthesis of 3-2-49

[1127] To a tetrahydrofuran solution (10 mL) containing SM-27-A (300 mg, 1.69 mmol) was added DIEA (873 mg, 6.75 mmol) and T7-4 (1045.23 mg, 5.07 mmol) at 0°C, 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 afford 3-2-49 as a white solid (196 mg, 33.4% yield). m / z calculated for [M+H] + 348.54,found 384.0.

[1128] 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).

[1129] Example 115. Preparation of Compound 3-2-50 of the Present Invention

[1130] Compound 3-2-50 was synthesized with reference to Example 110.

[1131] 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).

[1132] Example 116. Preparation of Compound 3-2-51 of the Present Invention

[1133] Compound 3-2-51 was synthesized according to Example 109.

[1134] 1 H 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).

[1135] Example 117. Preparation of Compound 3-2-52 of the Present Invention

[1136] 1. Synthesis of compound 110-3

[1137] Compound 110-3 was synthesized according to Example 1.

[1138] 2. Synthesis of compound INT-34

[1139] Dissolve 110-3 (1.12 g, 7.1 mmol) in dichloromethane at 0°C, add SM-45 (1.72 g, 10.6 mmol), and stir at 0°C for 4 hours. The reaction mixture was dried and purified by column chromatography to obtain the target product INT-34 in a yield of 77%.

[1140] 3. Synthesis of compound 3-2-52

[1141] 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 at room temperature overnight. After the reaction was complete, the reaction mixture was dried and passed through a column to obtain 140 mg of the target compound 3-2-52 in a 56% yield. MS (ESI) m / z: [M+H] + Calcd for C 17 H 26 N5O:316.2;Found:316.2.

[1142] 1 H 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).

[1143] Example 118. Preparation of Compound 3-2-53 of the Present Invention

[1144] 1. Synthesis of compound INT-35

[1145] Under argon, 4-tert-butylbenzonitrile SM-47 (847 μL, 5.0 mmol) was dissolved in tetrahydrofuran (13 mL) and cooled to –78°C. (TMP)2Cu(CN)Li2 was slowly added to the reaction solution, and the reaction mixture was allowed to react at 0°C for 2 hours. The reaction mixture was cooled again to –78°C, followed by the addition of benzylhydroxylamine (1.17 mL, 10.0 mmol), and then allowed to react at room temperature. After completion of the reaction, the mixture was quenched with saturated ammonium chloride and saturated sodium thiosulfate solutions. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 3:1) to afford INT-35 as a brown oil (720 mg, 83% yield).

[1146] 2. Synthesis of compound INT-36

[1147] 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 iodomethane (2.49 mL, 40.0 mmol) at 50°C for 48 hours. The mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford INT-36 (456 mg, 56% yield) as a yellow oil.

[1148] 3. Synthesis of compound INT-37

[1149] INT-36 (456 mg, 2.2 mmol) was dissolved in diethyl ether (6 mL), and lithium aluminum hydride (168 mg, 4.4 mmol, 2.0 equiv) was slowly added portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, 3 mL of 15% NaOH solution was added to quench the reaction, followed by 3 mL of water and then 3 mL of 15% sodium hydroxide solution. The mixture was filtered through celite and anhydrous sodium sulfate, and concentrated under reduced pressure to afford INT-37 (450 mg, 99% yield) as a yellow oil.

[1150] 4. Synthesis of compound INT-13

[1151] Compound INT-13 was synthesized according to Example 82.

[1152] 5. Synthesis of compound 3-2-53

[1153] INT-37 (248 mg, 1.2 mmol) was dissolved in toluene (2 mL), and thioisocyanate INT-13 (155 mg, 1.0 mmol) was added. After the reaction was complete, column chromatography (DCM / MeOH = 20:1) afforded 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.

[1154] 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).

[1155] Example 119. Preparation of Compound 3-2-54 of the Present Invention

[1156] 1. Synthesis of compound INT-38

[1157] 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 reacted 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 purified by column chromatography to afford INT-38 (790 mg, 98.7% yield) as a yellow oil.

[1158] 2. Synthesis of compound INT-39

[1159] 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 and stirred at 80°C. The mixture was cooled to room temperature, 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 obtain INT-39 as a yellow oil, which was used directly in the next step.

[1160] 3. Synthesis of compound INT-40

[1161] INT-39 was dissolved in tetrahydrofuran (10 mL). Lithium aluminum hydride (182 mg, 4.8 mmol) was slowly added portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 hours. Ethyl acetate (20 mL) was added to dilute the mixture, followed by quenching with 15% sodium hydroxide solution (3 mL). After stirring at room temperature for 15 minutes, celite was added and stirred until uniform. The mixture was filtered through celite. The filtrate was washed with water, dried, and concentrated under reduced pressure to afford INT-40 (330 mg, 35% yield) as a yellow oil.

[1162] 4. Synthesis of compound INT-13

[1163] Compound INT-13 was synthesized according to Example 82.

[1164] 5. Synthesis of compound 3-2-54

[1165] 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 compound 3-2-54 as a white solid (76% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H24 N3S2 + 346.1406; Found 346.1409

[1166] 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).

[1167] Example 120. Preparation of Compound 3-2-55 of the Present Invention

[1168] 1. Synthesis of compound INT-40

[1169] A solution of ZnCl2 (1.22 g, 9 mmol) in 2-methyltetrahydrofuran (10 mL) was cooled to –78°C and n-butyllithium (5.8 mL, 14.4 mmol, 2.5 M in tetrahydrofuran) was added dropwise. After addition, the mixture was warmed to room temperature and stirred for 20 minutes. This solution was added to a stirred mixture of SM-49 (732 mg, 3 mmol) and Pd(t-Bu3P)2 (153 mg, 0.3 mmol) and allowed to react at room temperature for 2 hours. 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 purified by column chromatography to afford INT-40 (417 mg, 80% yield) as a white solid.

[1170] 2. Synthesis of compound INT-41

[1171] 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 and 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 afford INT-41 as a yellow oil, which was used directly in the next step.

[1172] 3. Synthesis of compound INT-42

[1173] INT-41 was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (182 mg, 4.8 mmol, 2 equiv.) was slowly added portionwise at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and 15% sodium hydroxide solution (3 mL) was added to quench the mixture. After stirring at room temperature for 15 minutes, celite was added and stirred until uniform. The mixture was filtered through celite, dried, and concentrated under reduced pressure. Column chromatography afforded INT-42 (175 mg, 35% yield) as a yellow oil.

[1174] 4. Synthesis of compound 3-2-55

[1175] 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 afforded compound 3-2-55 as a white solid (175 mg, 63% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 19 H 28 N3O2 + 330.2176; Found 330.2184

[1176] 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),6.18(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, 5.0 Hz, 2H), 1.38 (dt, J = 14.6, 7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[1177] Example 121. Preparation of Compound 3-2-56 of the Present Invention (P3-5-2-2)

[1178] 1. Synthesis of compound 274-4

[1179] Compound 274-4 was synthesized with reference to Example 98.

[1180] 2. Synthesis of compound 3-2-56

[1181] 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 added to the system and stirred at room temperature for two hours. 274-4 (320 mg, 1.77 mmol) was then added to the system and allowed to react at room temperature overnight. After the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography and reverse synthesis to obtain 3-2-56 (170.72 mg, yield: 28.7%) as a white solid. ESI [M+H] + =337.4[M+H] + .

[1182] 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).

[1183] Example 122. Preparation of Compound 3-2-57 of the Present Invention (P3-2-1-5)

[1184] 1. Synthesis of 280-3

[1185] Compound 280-3 was synthesized according to Example 13.

[1186] 2. Synthesis of compound INT-13

[1187] Compound INT-13 was synthesized according to Example 82.

[1188] 3. Synthesis of compound 3-2-57

[1189] Compound 280-3 (483.86 mg, 3.22 mmol) and DIEA (2 mL) were added to a solution of compound INT-13 (500 mg, 3.22 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 80°C for 3 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford compound 3-2-57 (275 mg, 28% yield) as a light purple solid. m / z calculated for [M+H] + 306.5,found 306.1.

[1190] 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).

[1191] The beneficial effects of the present invention are demonstrated below through specific test examples.

[1192] Test Example 1: Study on the potent analgesic effect of the compounds of the present invention

[1193] 1 Test method

[1194] The loss of tail withdrawal reflex (LOTWR) in rats was used as the evaluation index to evaluate the potent analgesic effect of the compounds of the present invention.

[1195] 1.1 Experimental Animals: Adult male Sprague-Dawley rats weighing 220–300 g were selected for the experiment. Rats were housed in sawdust-based cages at 25 ± 1°C, 40%–60% humidity, and a 12-h light / 12-h dark cycle. No more than five rats were housed per cage, with free access to water and food.

[1196] 1.2 Experimental plan:

[1197] (1) The compound of the present invention, the positive control drug remifentanil, and the negative control group (vehicle) were administered in fixed volumes. The lowest effective dose of the compound of the present invention that produced a potent analgesic effect and the lowest dose that caused severe adverse reactions were determined using a dose escalation method.

[1198] (2) The duration of LOTWR for 30 seconds was used as the criterion for the production of a strong analgesic effect. During the experiment, the drug was administered through the rat's tail vein, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. Then, an alligator clip was used to clamp the rat's tail 1 cm away from the base, clamping it once longitudinally and transversely and leaving it in place, while continuously oscillating the distal end of the alligator clip (30 times / min) to continuously produce stimulation. When the rat had an escape reaction (i.e., escape movements, struggles, and squeaking) or the alligator clip stayed on the tail for 30 seconds (to avoid tissue damage), the clip was removed. If the rat had an escape reaction, the time point was recorded as no LOTWR, and the process was repeated every 2 minutes. When all the results were "no LOTWR" at 10 minutes (5 tests), the test was stopped and recorded as "invalid".

[1199] (3) All compounds will be dosed over a range of doses, starting at 1 mg / kg (due to the high potency of remifentanil, the lowest dose is set at 1 μg / kg), followed by 5 mg / kg, 10 mg / kg, 20 mg / kg, and so on (increased by 20 mg / kg each time after 20 mg / kg). Dose escalation will be stopped when the rats die. The lowest effective dose and the lowest dose that causes severe adverse reactions will be recorded throughout the entire process. In this study, severe adverse reactions are defined as: apnea, rigidity, convulsions, opisthotonos, convulsions, etc.

[1200] 1.3 Evaluation indicators: minimum effective dose; minimum dose that causes serious adverse reactions; therapeutic safety index = "minimum dose that causes serious adverse reactions" / "minimum effective dose".

[1201] 2 Test results

[1202] Table 1. Effectiveness and safety window of the compounds of the present invention in rats (single intravenous injection)

[1203] Remark:

[1204] “—” means the test was completed, but it did not work or had no such effect;

[1205] “A” means the lowest effective dose is ≤10.00 mg / kg;

[1206] "B" means 10.00 mg / kg < minimum effective dose ≤ 20.00 mg / kg;

[1207] "C" means 20.00 mg / kg < minimum effective dose ≤ 30.00 mg / kg;

[1208] "D" indicates that the minimum effective dose is greater than 30.00 mg / kg.

[1209] “+” indicates a safe therapeutic index ≤ 2;

[1210] “++” means 2<safe therapeutic index ≤ 4;

[1211] “+++” indicates a therapeutic safety index > 4.

[1212] As shown in Table 1, the compounds of the present invention and the μ-opioid receptor agonist remifentanil can both produce definite systemic potent analgesic effects. At the same time, as shown in the table, compared with the μ-opioid receptor agonist remifentanil, the safety therapeutic index of most of the compounds of the present invention is significantly improved, indicating that the compounds of the present invention have better safety.

[1213] The present invention provides a compound having analgesic effects. The compound has excellent analgesic effects, good safety, minimal toxic side effects, and does not cause dependence during use. Therefore, the compound has broad application prospects in the preparation of analgesic drugs and provides a new option for the clinical preparation of analgesic drugs.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof: in, R1 and R4 are independently selected from hydrogen or NR6R7, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, substituted or unsubstituted C1-C6 alkyl, OR 1a , R 1a is selected from C1-C6 alkyl, phenyl, and one or more of R1 and R4 is selected from NR6R7; R2, R3, and R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (CH2) p CONHR 1b , halogen, hydroxyl; p is an integer selected from 0 to 5, R 1b Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is an integer selected from 0 to 5; n is an integer selected from 0 to 5; X1, X2 are independently selected from O, S, NR8; Each R8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; L is selected from C=X3, substituted or unsubstituted 4- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1 to 5; When ring A is When X1 and X2 are both NH, L is C=O, m is 0, and n is 1, Not for When ring A is When X1 and X2 are both NH, L is C=O, and m and n are 0, Not for When ring A is When X1 and X2 are both NH, L is C=NH, m is 1, and n is 2, Not for 2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula IIa or formula IIb: in, R2 and R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (CH2) p CONHR 1b , halogen, hydroxyl; p is an integer selected from 0 to 5, R 1b Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; X1, X2 are independently selected from O, S, NR8; Each R8 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; L is selected from C=X3, substituted or unsubstituted 4- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =O; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

3. The compound according to claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula IIIa or IIIb: in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; X1, X2 are independently selected from O, S, NR8; Each R8 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; L is selected from C=X3, substituted or unsubstituted 4- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; or two substituents on the same atom form =O; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: X1, X2 are independently selected from O, S, NH; and / or, L is selected from X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

5. The compound according to claim 4, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: Selected from X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

6. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is shown in formula IV: in, 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 is selected from C1-C6 alkyl, phenyl, and one or more of R1 and R4 is selected from NR6R7; R2, R3, and R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (CH2) p CONHR 1b , halogen, hydroxyl; p is selected from 0, 1, 2, 3, 4 or 5, R 1b Selected from C1-C6 alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 Alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; X1, X2 are independently selected from O, S, NR8; Each R8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 8-membered heteroaryl and 5- to 8-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

7. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula IVa: in, 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 is selected from C1-C6 alkyl, phenyl, and one or more of R1 and R4 is selected from NR6R7; R2, R3, and R5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

8. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula Va or Vb: in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

9. The compound according to claim 8, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula VIa or VIb: in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

10. The compound according to claim 8, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula VIIa or VIIb: in, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, NR6R7, (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, 3-4 membered heterocycloalkyl; R6 and R7 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; X3 is selected from O, S, NR9, CR 10 R 11 ; R9 is selected from hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 10 , R 11 are independently selected from hydrogen, cyano, nitro, -C(O)R 12 , substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; R 12 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted 5- to 6-membered heteroaryl and 6-membered aryl; The number of substituents of the alkyl group and the alkoxy group is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The number of substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is one or two or more, and each substituent is independently selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatoms in the heterocycloalkyl and heteroaryl groups are O, S and / or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

11. The compound according to any one of claims 1 to 3 or 5 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof, characterized in that: Ring A is selected from the following substituted or unsubstituted groups: The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy; Preferably, the substituents of ring A are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy.

12. The compound according to any one of claims 1 to 3 or 5 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof, characterized in that: The compound is one of the following compounds:

13. A method for preparing the compound according to any one of claims 1 to 12, 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, characterized in that: It includes the following steps: In a solvent, compound a, an organic base, TCDI or CDI and compound b react to obtain a compound represented by formula IV; R1, R2, R3, R4, R5, m, n, X1, X2, A ring as described in any one of claims 1 to 12; X3 is S or O; Preferably, The solvent is dichloromethane; And / or, the organic base is Et3N; And / or, the reaction temperature is 25-40° C., and the reaction time is 10-12 hours.

14. A method for preparing the compound according to any one of claims 1 to 12, 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, characterized in that: It includes the following steps: Step 1: Compound c reacts with CH3I in a solvent to obtain compound d; Step 2: Compound d reacts with aqueous ammonia in a solvent to obtain a compound represented by formula IVa; R1, R2, R3, R4, R5, m, n, and A ring are as described in any one of claims 1 to 12; Preferably, In step 1, the solvent is acetonitrile; And / or, in step 1, the reaction temperature is 40 to 60° C., and the reaction time is 4 to 10 hours; And / or, in step 2, the solvent is acetonitrile; And / or, in step 2, the reaction temperature is 80-100° C., and the reaction time is 10-12 hours.

15. Use of the compound according to any one of claims 1 to 12, 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 in the preparation of a drug having analgesic effect.

16. A drug, characterized in that: It is a preparation prepared with the compound described in any one of claims 1 to 12, 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, and pharmaceutically acceptable excipients.

17. A pharmaceutical composition, characterized in that: It includes the compound described in any one of claims 1 to 12, 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.

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