Complex ring-substituted pyrimidopyran compounds and their use

Abstract

The present invention discloses a heterocyclic ring-substituted pyrimidopyran compound and its use, specifically, a compound represented by formula (VII) and a pharmaceutically acceptable salt thereof. 【Chemical 1】 TIFF2025520714000387.tif45164

Description

Technical Field

[0001] The present invention claims priority from the following: CN202210731477.1 (filing date: June 24, 2022), CN202210743845.4 (filing date: June 27, 2022), CN202210969097.1 (filing date: August 12, 2022), CN202211494347.7 (filing date: November 25, 2022), CN202310010084.6 (filing date: January 4, 2023), CN202310082801.6 (filing date: February 3, 2023), and CN202310206933.5 (filing date: March 6, 2023). The present invention relates to a heterocyclic substituted pyrimidopyran compound and its use, and specifically discloses a compound represented by formula (VII) and its pharmaceutically acceptable salts.

[0002]

Background Art

[0003] RAS gene mutations are the most common activating mutations in human cancers and occur in approximately 30% of human tumors. The RAS gene family consists of three subtypes (KRAS, HRAS, and NRAS), and 85% of RAS-driven cancers are caused by mutations in the KRAS subtype. KRAS is a cancer gene of murine sarcoma virus and an important member of the RAS protein. KRAS is like a molecular switch and can control the cell proliferation pathway in a normal state. After mutation, the KRAS gene can transmit growth and proliferation signals to downstream pathways independently without depending on upstream growth factor receptor signals. As a result, cell proliferation is not controlled and tumors progress. At the same time, whether the KRAS gene has a mutation is also an important indicator for the prognosis of tumors.

[0004] ​KRAS mutations are common in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS mutant tumors, 80% of the oncogenic mutations occur at codon 12, and the most common mutations include p.G12D (41%), p.G12V (28%), and p.G12C (14%). In the United States, there are approximately 166,000 new patients with single KRAS mutations (G12D and G12V mutations account for the largest proportion), approximately 9,000 new patients with KRAS amplification, and approximately 4,000 new patients with multiple KRAS mutations. Currently, there is a lack of effective targeted therapeutic drugs in the overwhelming majority of patients.

[0005] So far, small molecules that directly target KRAS mutations mainly focus on the KRAS G12C region. Among them, Amgen's AMG510 and Mirati Therapeutics' MRTX849 have received manufacturing and sales approvals and have shown good therapeutic effects on patients with KRAS G12C mutant tumors. However, small molecules that target all KRAS mutations still have not entered the clinical research stage, and tumor patients with all KRAS mutations and KRAS amplification have not benefited from accurate medical treatment.

Summary of the Invention

[0006] The present invention provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

[0007] The present invention further provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0008] The present invention further provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] The present invention further provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

[0010] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (V-1),

Chemical formula

[0011] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (V-1),

Chemical formula

[0012] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (IV-3),

Chemical formula

[0013] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (IV-1), [Chemical formula] wherein, R1, R2, ring B, and m are as defined herein.

[0014] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (P-1), [Chemical formula] wherein, ring B is [Chemical formula] and 5- to 12-membered heterocyclic alkenyl, and [Chemical formula] selected from [Chemical formula] and the 5- to 12-membered heterocyclic alkenyl are each independently and optionally substituted with 1, 2, 3, 4, 5 or 6 R e groups, R1, R2, R6, R7, each R e , ring C, and m are as defined herein, the carbon atom marked with "*" is a chiral carbon atom and exists in the form of a single enantiomer of (R) or (S), or in an enantiomerically enriched form.

[0015] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (P-2), [Chemical formula] wherein, ring B is [Chem.] selected from [Chem.] R, independently and optionally, is substituted with one, two, three, four, five or six R e and p is selected from 1, 2, 3, 4, or 5, R1, each R e each R d and m are as defined herein, the carbon atom marked with "*" is a chiral carbon atom and exists in the form of a single enantiomer of (R) or (S), or in an enantiomerically enriched form.

[0016] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formulas (P-2-1), (P-2-2), and (P-2-3), [Chem.] wherein p is selected from 1, 2, 3, 4, or 5, R1, R e each R d and m are as defined herein, the carbon atom marked with "*" is a chiral carbon atom and exists in the form of a single enantiomer of (R) or (S), or in an enantiomerically enriched form.

[0017] In some embodiments of the present invention, among the compounds or their pharmaceutically acceptable salts, the compound is selected from formula (IV-2), [Chem.] wherein ring A is [Chem.] selected from or ring A is

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0018] In some embodiments of the present invention, among the compounds or pharmaceutically acceptable salts thereof, the compound is selected from formula (I-1),

Chemical formula

Chemical formula

[0019] In some embodiments of the present invention, each R is independently selected from F, Cl, Br, I, CH3, CH2CH3, and CH2CH2CH3, and the other variables are as defined herein.

[0020] In some embodiments of the present invention, R is selected from F and CH3, and the other variables are as defined herein.

[0021] In some embodiments of the present invention, R0 is selected from D, and the other variables are as defined herein.

[0022] In some embodiments of the present invention, R ais selected from H, CH3, CD3, and CH(CH3)2, and the other variables are as defined herein.

[0023] In some embodiments of the present invention, R a is selected from H, CH3, and CH(CH3)2, and the other variables are as defined herein.

[0024] In some embodiments of the present invention, R b is selected from H, CH3, CD3, and CH(CH3)2, and the other variables are as defined herein.

[0025] In some embodiments of the present invention, R b is selected from H, CH3, and CH(CH3)2, and the other variables are as defined herein.

[0026] In some embodiments of the present invention, R c is selected from H, cyclopropyl, tetrahydropyrrolyl, and morpholinyl, and the other variables are as defined herein.

[0027] In some embodiments of the present invention, R c is selected from tetrahydropyrrolyl and morpholinyl, and the other variables are as defined herein.

[0028] In some embodiments of the present invention, R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CF2H, CF3, CH2CH3, CF2CF3,

Chemical formula

[0029] In some embodiments of the present invention, R dare each independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3,

Chem.

[0030] In some embodiments of the present invention, R e is each independently selected from H and F, and the other variables are as defined herein.

[0031] In some embodiments of the present invention, T1 is selected from CH, and the other variables are as defined herein.

[0032] In some embodiments of the present invention, T1 is selected from O, and the other variables are as defined herein.

[0033] In some embodiments of the present invention, T2 is selected from O, and the other variables are as defined herein.

[0034] In some embodiments of the present invention, R1 is independently F, Cl, Br, I, OH, NH2, CN,

Chem.

Chem.

Chem.

Chem.

[0035] In some embodiments of the present invention, R1 is F, Cl, Br, I, OH,

Chem.

[0036] In some embodiments of the present invention, R1s are each independently F, Cl, Br, OH, NH2, CN, CH3, CH(CH3)2,

Chem.

Chem.

[0037] In some embodiments of the present invention, each R1 is independently F, Cl, OH, NH2, CN, CH3, CH(CH3)2,

Chemical formula

Chemical formula

[0038] In some embodiments of the present invention, each R1 is F, Cl, OH, CH3, CF3,

Chemical formula

[0039] In some embodiments of the present invention, R1 is F, Cl, OH, CH3,

Chemical formula

[0040] In some embodiments of the present invention, R2 is selected from phenyl, naphthyl, indolyl, pyridyl, pyrrolyl, benzopyrimidinyl, and quinolyl, and phenyl, naphthyl, indolyl, pyridyl, pyrrolyl, benzopyrimidinyl and quinolyl are each independently and optionally substituted with 1, 2, 3, 4 or 5 R d and the other variables are as defined herein.

[0041] In some embodiments of the present invention, R2 is selected from phenyl, naphthyl, and pyridyl, and phenyl, naphthyl, and pyridyl are each independently and optionally substituted with 1, 2, 3, 4 or 5 R dis replaced, and the other variables are as defined herein.

[0042] In some embodiments of the present invention, R2 is selected from phenyl and naphthyl, and phenyl and naphthyl are each independently and optionally substituted with 1, 2, 3, 4 or 5 R d is replaced, and the other variables are as defined herein.

[0043] In some embodiments of the present invention, R2 is

Chemical formula

[0044] In some embodiments of the present invention, R2 is

Chemical formula

[0045] In some embodiments of the present invention, R2 is

Chemical formula

[0046] In some embodiments of the present invention, ring C is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, and pyrimidinyl, and the other variables are as defined herein.

[0047] In some embodiments of the present invention, ring C is selected from pyrazolyl and imidazolyl, and the other variables are as defined herein.

[0048] In some embodiments of the present invention, ring A is [Chemical formula] selected from, and the other variables are as defined herein.

[0049] In some embodiments of the present invention, ring A is [Chemical formula] selected from, and the other variables are as defined herein.

[0050] In some embodiments of the present invention, ring A is [Chemical formula] selected from, and the other variables are as defined herein.

[0051] In some embodiments of the present invention, ring A is [Chemical formula] selected from, and the other variables are as defined herein.

[0052] In some embodiments of the present invention, ring B is selected from 8- to 9-membered heterocyclic alkenyl, and the other variables are as defined herein.

[0053] In some embodiments of the present invention, ring B is [Chemical formula] 5- to 12-membered heterocyclic alkenyl, 7- to 12-membered tricyclic heterocyclic alkyl, and [Chemical formula] selected from, [Chemical formula] The 5- to 12-membered heterocyclic alkenyl and the 7- to 12-membered tricyclic heterocyclic alkyl are each independently and optionally substituted with 1, 2, 3, 4, 5 or 6 Rs e and the other variables are as defined herein.

[0054] In some embodiments of the present invention, ring B is

Chemical formula

Chemical formula

Chemical formula

[0055] In some embodiments of the present invention, ring B is

Chemical formula

[0056] In some embodiments of the present invention, ring B is

Chemical formula

[0057] In some embodiments of the present invention, the structural unit

Chemical formula

[0058] In some embodiments of the present invention, the structural unit [Chemical formula] is [Chemical formula] selected from, and the other variables are as defined herein.

[0059] In some embodiments of the present invention, the structural unit [Chemical formula] is [Chemical formula] selected from, and the other variables are as defined herein.

[0060] In some embodiments of the present invention, ring A is [Chemical formula] selected from, and ring B is [Chemical formula] selected from, and the other variables are as defined herein.

[0061] In some embodiments of the present invention, ring A is [Chemical formula] selected from, and ring B is [Chemical formula] selected from, and other variables are as defined herein.

[0062] In some embodiments of the present invention, R1 on two adjacent atoms forms a 5- to 6-membered heterocyclic alkenyl together with the atoms to which they are attached, and the 5- to 6-membered heterocyclic alkenyl is independently and optionally substituted with 1, 2, 3, 4 or 5 R's, and thus the structural unit

Chemical formula

Chemical formula

[0063] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

Chemical formula

[0064] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

Chemical formula

[0065] In some embodiments of the present invention, the structural unit [Chem.] is selected from [Chem.] and other variables are as defined herein.

[0066] In some embodiments of the present invention, the structural unit [Chem.] is selected from [Chem.] and other variables are as defined herein.

[0067] In some embodiments of the present invention, the structural unit [Chem.] is selected from [Chem.] [Chem.] and other variables are as defined herein.

[0068] In some embodiments of the present invention, the structural unit [Chem.] is selected from [Chem.] and other variables are as defined herein.

[0069] In some embodiments of the present invention, ring B is [Chemical formula] selected from, and the structural unit [Chemical formula] is [Chemical formula] [Chemical formula] selected from, and the other variables are as defined herein.

[0070] In some embodiments of the present invention, ring B is [Chemical formula] selected from, and the structural unit [Chemical formula] is [Chemical formula] [Chemical formula] selected from, and the other variables are as defined herein.

[0071] In some embodiments of the present invention, the structural unit [Chemical formula] is [Chemical formula] [Chemical formula] selected from, and ring B is [Chemical formula] selected from, and the other variables are as defined herein.

[0072] In some embodiments of the present invention, the structural unit

Chemical formula

Chemical formula

Chemical formula

[0073] In some embodiments of the present invention, R6 is selected from H, and the other variables are as defined herein.

[0074] In some embodiments of the present invention, R7 is selected from H, and the other variables are as defined herein.

[0075] The present invention further provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0076] The present invention further provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0077] The present invention further provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

[0078] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R a is selected from H, CH3, and CH(CH3)2, and the other variables are as defined herein.

[0079] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R b is selected from H, CH3, and CH(CH3)2, and the other variables are as defined herein.

[0080] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R c is selected from tetrahydropyrrolyl and morpholinyl, and the other variables are as defined herein.

[0081] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, each R d is independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CF2H, CF3, CH2CH3, CF2CF3,

Chemical formula

[0082] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, each R d is independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3,

Chemical formula

[0083] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R1 is selected from F, Cl, OH, CH3,

Chemical formula

[0084] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R2 is selected from phenyl and naphthyl, and phenyl and naphthyl are each independently and optionally substituted with 1, 2, 3, 4 or 5 R d and the other variables are as defined herein.

[0085] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R2 is

Chemical formula

[0086] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, R2 is

Chemical formula

[0087] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, ring A is

Chemical formula

[0088] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the structural unit

Chemical formula

Chemical formula

[0089] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the structural unit

Chemical formula

Chemical formula

[0090] In some embodiments of the present invention, for the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the structural unit

Chemical formula

Chemical formula

[0091] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the structural unit

Chemical formula

Chemical formula

[0092] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the structural unit

Chemical formula

Chemical formula

[0093] In some embodiments of the present invention, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the structural unit

Chemical formula

Chemical formula

[0094] There are also some embodiments of the present invention that can be obtained by appropriately combining the above variables.

[0095] The present invention provides the following compounds or pharmaceutically acceptable salts:

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0096] In some embodiments of the present invention, the compound or its pharmaceutically acceptable salt is selected from the following:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0097] The present invention further provides the following synthesis methods: Synthesis method 1: [Chemistry] Synthesis method 2: [Chemistry]

[0098] The present invention further provides the use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating all KRAS-related diseases.

[0099] The present invention further provides the use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumor-related diseases.

[0100] Test method 1: H358 cell experiment 1. Purpose of the experiment To test the IC 50 of the compound for inhibiting the growth of H358 cells.

[0101] 2. Reagents The main reagents used in the research include RPMI-1640 medium, penicillin / streptomycin antibiotics (purchased from Wisent), and fetal bovine serum (purchased from Biosera). The CellTiter-Glo (Cell viability chemiluminescence assay) reagent was purchased from Promega. The NCI-H358 cell line was purchased from the Chinese Academy of Sciences Cell Bank.

[0102] 3. Equipment The main equipment used in the research is the Nivo multi-label analyzer (PerkinElmer).

[0103] 4. Methods: 1) Seed NCI-H358 cells in a white 96-well plate at a density of 80 μL of cell suspension per well (containing 4,000 NCI-H358 cells). Incubate the cell plate overnight in a carbon dioxide incubator.

[0104] 2) Using a multi-channel pipette, perform a 5-fold dilution of the test compound up to the 9th concentration (i.e., from 2 mM to 5.12 nM) and duplicate it. Add 78 μL of medium to an intermediate plate, then transfer the serially diluted compound to the intermediate plate at a density of 2 μL per well according to the corresponding positions, mix, and transfer it to the cell plate at a density of 20 μL per well. The concentration range of the compound transferred into the cell plate is 10 μΜ - 0.0256 nM. Incubate the cell plate in a carbon dioxide incubator for 5 days. Prepare another cell plate and use the signal value read on the addition day as the maximum value (Max value in the following formula) for data analysis. Add the CellTiter-Glo (Cell viability chemiluminescence assay) reagent to the cell plate at a density of 25 μL per well and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Readings are performed using a multi-label analyzer.

[0105] 3) Add the chemiluminescence assay reagent for cell viability to the cell plate at a density of 25 μL per well and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Reading is performed using a multi-label analyzer.

[0106] Data analysis: Convert the original data to the inhibition rate using the formula (Sample - Min) / (Max - Min)×100%, and obtain the IC 50 value by four-parameter curve fitting (GraphPad Prism "log(inhibitor) vs. response - Variable slope" mode).

[0107] Test method 2. Antiproliferative effect of the compound on the tumor cell line AsPC-1 Research objective This experiment studies the antiproliferative effect of the compound by detecting the effect of the compound on the in vitro cell viability of the tumor cell line AsPC-1.

[0108] Experimental materials

Table 1

[0109] Ultra Low Cluster-96 well plate (Corning-7007)

[0110] Greiner CELLSTAR 96 well plate (#655090)

[0111] Promega CellTiter-Glo 3D luminescence cell viability assay kit (Promega-G9683)

[0112] 2104-10 EnVision reader (PerkinElmer)

[0113] RPMI 1640, DMEM, PBS (Phosphate Buffered Saline), FBS (Fetal Bovine Serum), antibiotics - antifungal agents, L - glutamine, and DMSO (Dimethyl Sulfoxide)

[0114] Experimental methods and steps Cell culture Under the culture conditions shown in the culture method, the tumor cell line is incubated in an incubator at 37°C and 5% CO2. Passage is carried out as usual, and cells in the logarithmic growth phase are collected and seeded.

[0115] Cell seeding The cells are stained with trypan blue and the number of viable cells is counted.

[0116] The cell concentration is adjusted to an appropriate concentration.

Table 2

[0117] The cell suspension is added to the ULA culture plate at a density of 135 μL per well, and an equal volume of cell - free medium is added to the blank control plate.

[0118] After seeding, the ULA culture plate is immediately centrifuged at room temperature at 1,000 rpm for 10 minutes. Note: To avoid unnecessary shaking, all subsequent operations after centrifugation should be carried out with caution.

[0119] The culture plate is incubated overnight in an incubator at 37°C, 5% CO2, and 100% relative humidity.

[0120] Preparation of 10X compound standard solution and cell treatment with the compound (Day 1) After preparing the 10X compound standard solution (DMSO 10X standard solution), 15 μL of the 10X compound standard solution is added to the ULA culture plate, and 15 μL of the DMSO - cell medium mixture is added to the vehicle control and the blank control.

[0121] Return the 96-well cell plate to the incubator and incubate for 120 hours.

[0122] Observe the spheroid formation of the cells daily until the end of the experiment.

[0123] CellTiter-Glo Luminescent Cell Viability Assay (Day 5) Perform the following steps according to the instructions of the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0124] Add CellTiter-Glo 3D reagent at a density of 150 μL per well (equal to the volume of cell culture medium per well). Wrap the cell plate with aluminum foil to avoid light.

[0125] Shake the culture plate on an orbital shaker for 5 minutes.

[0126] Carefully aspirate and dispense the mixture with a pipette 10 times to mix the mixture in the well. Before proceeding to the next step, make sure the cell spheroids are well separated.

[0127] Then, transfer the solution in the ULA plate to a black plate (#655090) and leave it at room temperature for 25 minutes to stabilize the luminescence signal.

[0128] Detect the luminescence signal with a 2104 EnVision reader.

[0129] Data analysis The inhibition rate (IR) of the detected compound is calculated using the following formula: IR (%) = (1 - (RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control)) × 100%. Calculate the inhibition rate of the compound at various concentrations in Excel, and then create an inhibition curve diagram to obtain the minimum inhibition rate, maximum inhibition rate, and IC 50Calculate the relevant parameters including

[0130] Technical effects The compounds of the present invention have good inhibitory activity against multiple KRAS mutant cells and KRAS amplified cells, and show good tumor inhibitory effects in GP2D cell line and Panc0403 cell line.

[0131] Related definitions Unless otherwise specified, the following terms and phrases used in this specification are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear even if not specifically defined, but should be understood in its ordinary meaning. When a trade name is listed in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0132] As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms that are within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic reaction, or other problems or complications, and exhibit a reasonable benefit / risk ratio.

[0133] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from compounds having the specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain compounds of the present invention contain both basic and acidic functional groups and can thus be converted into any base addition salt or acid addition salt.

[0134] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acidic or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting a compound in free acid or free base form with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both.

[0135] Unless otherwise specified, the term "treatment" is intended to refer to all processes that may slow, interrupt, control, or stop the progression of a disease, but does not necessarily mean the elimination of all symptoms.

[0136] The compounds of the present invention may exist in the form of specific geometric or stereoisomers. In the present invention, all such compounds (including cis and trans isomers, (-) and (+) enantiomers, (R) and (S) enantiomers, diastereomers, (D) isomers, (L) isomers, their racemic mixtures, and other mixtures such as enantiomerically or diastereomerically enriched mixtures) are contemplated to be within the scope of the present invention. Additional asymmetric carbon atoms may be present in alkyl and other substituents. All of these isomers and their mixtures are included within the scope of the present invention.

[0137] The compounds of the present invention may contain atomic isotopes in unnatural proportions for one or more of the atoms that make up the compound. For example, the compound may be labeled with a radioactive isotope such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For example, hydrogen may be replaced with deuterium to form a deuterated drug, and the bond formed by deuterium and carbon is stronger than the bond formed by normal hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxicity and side effects, increased drug stability, enhanced efficacy, and extended biological half-life of the drug. All isotope composition conversions of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0138] The terms "optional" or "optionally" mean that the event or circumstance described thereafter may occur but need not occur, and the description includes both the occurrence and non-occurrence of the described event or circumstance.

[0139] The term "substituted" means that any one or more hydrogen atoms on a particular atom are substituted with a substituent (which may include deuterium and variants of hydrogen), provided that the valence of the particular atom is standard and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. The term "optionally substituted" means "may or may not be substituted", and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0140] In the composition or structure of a compound, when any variable (e.g., R) appears more than once, the definition of the variable in each instance is independent. Thus, for example, if a group is substituted with 0 to 2 Rs, the group may optionally be substituted with up to 2 Rs, and in each instance, R has independent choices. Further, combinations of substituents and / or their variants are permitted only if the compound is stable by such combinations.

[0141] When the number of linking groups is 0 (e.g., -(CRR)0-), it is indicated that the linking group is a single bond.

[0142] When one of the variables is selected from a single bond, it is indicated that the two groups thereby linked are directly linked. For example, when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.

[0143] When the described linking group does not indicate a linking direction, the linking direction is arbitrary. For example,

Chemical formula

Chemical formula

Chemical formula

[0144] Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of that group can be linked to other groups by chemical bonds. When the chemical bond is linked non-positionally and the linking site has an H atom, the number of H atoms at the linking site can decrease according to the corresponding valence of the group in accordance with the number of linking chemical bonds. The chemical bond linking the site to another group is a solid straight line

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0145] Unless otherwise specified, in some embodiments of the present invention, when ring B is selected from [Chemical formula] , [Chemical formula] each is independently substituted with 1, 2, 3, 4, 5, or 6 Rs e , and the substitution is indicated as the substitution at the R [Chemical formula] of the hexahydro-1H-pyrrolidine ring e .

[0146] Unless otherwise specified, in some embodiments of the present invention, the structural fragment [Chemical formula] When it is replaced by R1, the replacement is indicated as the replacement at R1 of the piperidine ring

Chem.

[0147] Unless otherwise specified, the absolute configuration of the three-dimensional center is represented by the solid wedge bond

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0148] Unless otherwise specified, when a double bond structure is present in the compound (for example, carbon-carbon double bond, carbon-nitrogen double bond, and nitrogen-nitrogen double bond), and each atom on the double bond is linked to two different substituents (in the double bond containing a nitrogen atom, a pair of non-bonding electrons on the nitrogen atom is regarded as one of the linked substituents), if the atoms on the double bond in the compound are linked to their substituents with a wavy line

Chemical formula

Chemical formula

[0149] Unless otherwise specified, when a double bond structure is present in the compound (for example, carbon-carbon double bond, carbon-nitrogen double bond, and nitrogen-nitrogen double bond), and each atom on the double bond is linked to two different substituents (in the double bond containing a nitrogen atom, a pair of non-bonding electrons on the nitrogen atom is regarded as one of the linked substituents), in order to represent the between the atoms on the double bond in the compound and their substituents

Chemical formula

[0150] Unless otherwise specified, C n~n+m or C n ~C n+m includes every example containing n to n + m carbons (e.g., C 1~12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 ), and also includes every range from n to n + m (e.g., C 1~12 includes C 1~3 , C 1~6 , C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 , and C 9~12 ). Similarly, n~n + m means that the number of atoms in the ring is n to n + m (e.g., a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring), and also includes every range from n to n + m (e.g., a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring).

[0151] Unless otherwise specified, the terms "enriched in isomers", "isomers enriched", "enriched in enantiomers", or "enantiomers enriched" mean that the content of one of the isomers or enantiomers is less than 100% and the content of the isomers or enantiomers is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0152] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference in the relative proportions of two isomers or enantiomers. For example, when the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer excess or enantiomer excess (ee value) is 80%.

[0153] Unless otherwise specified, the term "halogenin" or "halogen" represents a fluorine, chlorine, bromine or iodine atom, either by itself or as part of another substituent.

[0154] Unless otherwise specified, "C 1~3 alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. C 1~3 alkyl includes C 1~2 and C 2~3 alkyl, etc., which can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of C 1~3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0155] Unless otherwise specified, "C 1~4The term "alkoxy" refers to an alkyl group containing 1 to 4 carbon atoms, which is linked to the remainder of the molecule by an oxygen atom. C 1~4 Alkoxy includes C 1~3 , C 1~2 , C 2~4 , C4 and C3 alkoxy, etc. C 1~4 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), etc.

[0156] Unless otherwise specified, "C 2~4 alkenyl" is used to represent a hydrocarbon group consisting of 2 to 4 carbon atoms, which contains at least one carbon-carbon double bond in a straight or branched chain, where the carbon-carbon double bond can be located anywhere in the group. C 2~4 Alkenyl includes C 2~3 , C4, C3 and C2 alkenyl, etc., and C 2~4 alkenyl can be monovalent, divalent, or polyvalent. C 2~4 Examples of alkenyl include, but are not limited to, vinyl, propylene, butenyl, butadienyl, etc. Unless otherwise specified, "C 2~3 alkenyl" is used to represent a hydrocarbon group consisting of 2 to 3 carbon atoms, which contains at least one carbon-carbon double bond in a straight or branched chain, where the carbon-carbon double bond can be located anywhere in the group. C 2~3 Alkenyl includes C3 and C2 alkenyl, and C 2~3 alkenyl can be monovalent, divalent, or polyvalent. C 2~3 Examples of alkenyl include, but are not limited to, vinyl, propylene, etc.

[0157] Unless otherwise specified, "C 2~4 alkynyl" is used to represent a hydrocarbon group consisting of 2 to 4 carbon atoms, which contains at least one carbon-carbon triple bond in a straight or branched chain, where the carbon-carbon triple bond can be located anywhere in the group. C2~4 Alkynyl includes C 2~3 , C4, C3, and C2 alkynyl, etc., and they can be monovalent, divalent, or polyvalent. C 2~4 Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, etc.

[0158] Unless otherwise specified, "C 3~6 cycloalkyl" represents a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and C 3~6 Cycloalkyl includes C 3~5 , C 4~5 and C 5~6 cycloalkyl, etc., and they can be monovalent, divalent, or polyvalent. C 3~6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0159] Unless otherwise specified, the term "5- to 12-membered heterocyclic alkenyl" represents, by itself or in combination with other terms, a partially unsaturated cyclic group consisting of 5 to 12 ring atoms each containing at least one carbon-carbon double bond, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. Here, the carbon atoms are optionally oxygenated (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Monocyclic, bicyclic, and tricyclic systems are included, and the bicyclic and tricyclic systems include spirocyclic, fused-ring, and bridged-ring systems, and all the rings of the system are non-aromatic. In addition, in the case of "5- to 12-membered heterocyclic alkenyl", the position where the heterocyclic alkenyl is linked to the rest of the molecule may be occupied by a heteroatom. 5- to 12-membered heterocyclic alkenyl includes 5- to 10-membered, 5- to 8-membered, 5- to 6-membered, 4- to 5-membered, 4-membered, 5-membered, and 6-membered heterocyclic alkenyl, etc.

[0160] Unless otherwise specified, the term "5- or 6-membered heterocyclic alkenyl", by itself or in combination with other terms, each represents a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, where 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. Here, the carbon atoms are optionally oxygenated (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Monocyclic and bicyclic systems are included, and the bicyclic systems include spirocyclic, fused-ring, and bridged-ring systems, and all the rings of the systems are non-aromatic. In addition, in the case of "5- or 6-membered heterocyclic alkenyl", the position where the heterocyclic alkenyl is linked to the rest of the molecule may be occupied by a heteroatom. The 5- or 6-membered heterocyclic alkenyl includes 5-membered and 6-membered heterocyclic alkenyl, etc. Examples of the 5- or 6-membered heterocyclic alkenyl include, but are not limited to, [Chemical formula] etc. are included.

[0161] Unless otherwise specified, the term "4- to 6-membered heterocyclic alkyl", by itself or in combination with other terms, each represents a saturated cyclic group consisting of 4 to 6 ring atoms, where 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. Here, the carbon atoms are optionally oxygenated (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). Monocyclic and bicyclic systems are included, and the bicyclic systems include spirocyclic, fused-ring, and bridged-ring systems. In addition, in the case of "4- to 6-membered heterocyclic alkyl", the position where the heterocyclic alkyl is linked to the rest of the molecule may be occupied by a heteroatom. The 4- to 6-membered heterocyclic alkyl includes 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocyclic alkyls, etc. Examples of 4- to 6-membered heterocyclic alkyls include, but are not limited to, azacyclobutyl, oxacyclobutyl, thiacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, etc.

[0162] Unless otherwise specified, the term "5- to 6-membered heterocyclic alkyl" represents, by itself or in combination with other terms, a saturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3, or 4 of which are independently heteroatoms selected from O, S, and N, and the rest are carbon atoms. Here, the carbon atoms are optionally oxygenated (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). Monocyclic and bicyclic systems are included, and the bicyclic systems include spirocyclic, fused-ring, and bridged-ring systems. In addition, in the case of "5- to 6-membered heterocyclic alkyl", the position where the heterocyclic alkyl is linked to the rest of the molecule may be occupied by a heteroatom. 5- to 6-membered heterocyclic alkyl includes 5-membered and 6-membered heterocyclic alkyl. Examples of 5- to 6-membered heterocyclic alkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0163] Unless otherwise specified, the term "7- to 12-membered tricyclic heterocyclic alkyl" represents, by itself or in combination with other terms, a tricyclic saturated cyclic group consisting of 7 to 12 ring atoms, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Here, the carbon atoms are optionally oxygenated (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). 7- to 12-membered tricyclic heterocyclic alkyl includes spirocyclic, fused-ring, and bridged-ring systems. In addition, in the case of "7- to 12-membered tricyclic heterocyclic alkyl", the position where the heterocyclic alkyl is linked to the rest of the molecule may be occupied by a heteroatom. 7- to 12-membered tricyclic heterocyclic alkyl includes 7- to 10-membered, 7- to 8-membered, 8- to 10-membered, 8- to 12-membered, 9- to 10-membered, 9- to 12-membered, 10- to 12-membered, 9-membered, and 10-membered heterocyclic alkyl, etc.

[0164] Unless otherwise specified, the terms "5- to 10-membered aromatic heterocycle" and "5- to 10-membered heteroaryl" in the present invention may be used interchangeably, and the term "5- to 10-membered heteroaryl" represents a cyclic group consisting of 5 to 10 ring atoms and having a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. The 5- to 10-membered heteroaryl may be a monocyclic, fused bicyclic, or fused tricyclic system, in which all rings are aromatic, the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5- to 10-membered heteroaryl can be linked to the remainder of the molecule by a heteroatom or a carbon atom. The 5- to 10-membered heteroaryl includes 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered and 6-membered heteroaryl, etc. Examples of the 5- to 10-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl, 6-quinolinyl, etc.).

[0165] Unless otherwise specified, the terms "5- or 6-membered aromatic heterocycle" and "5- or 6-membered heteroaryl" in the present invention can be used interchangeably. The term "5- or 6-membered heteroaryl" represents a monocyclic group consisting of 5 to 6 ring atoms and having a conjugated π-electron system, where 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5- or 6-membered heteroaryl can be linked to the remainder of the molecule by a heteroatom or a carbon atom. The 5- or 6-membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of 5- or 6-membered heteroaryls include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0166] Unless otherwise specified, the terms "5- or 6-membered nitrogen-containing aromatic heterocycle" and "5- or 6-membered nitrogen-containing heteroaryl" in the present invention can be used interchangeably. The term "5- or 6-membered nitrogen-containing heteroaryl" represents a monocyclic group consisting of 5 to 6 ring atoms and having a conjugated π electron system, wherein 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, at least one heteroatom is N, and the remainder are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5- or 6-membered heteroaryl can be linked to the remainder of the molecule by a heteroatom or a carbon atom. The 5- or 6-membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5- or 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0167] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art. Such methods include, but are not limited to, the specific embodiments listed below, embodiments resulting from combinations with other chemical synthetic methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0168] The compounds of the present invention can be structurally confirmed by conventional methods well-known to those skilled in the art. When the present invention relates to the absolute configuration of a compound, its absolute configuration can be confirmed by conventional technical means in the art. For example, using the single crystal X-ray diffraction (SXRD) method, with the light source being CuΚα ray and the scanning mode being φ / ω scan, diffraction intensity data is collected from the grown single crystal by a Bruker D8 venture diffractometer. After collecting the relevant data, the crystal structure is further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.

[0169] The solvents used in the present invention are commercially available. The following abbreviations are used in the present invention: DMF is N,N-dimethylformamide, DIPEA is N,N-diisopropylethylamine, DCM is dichloromethane, m-CPBA is m-chloroperbenzoic acid, NBS is N-bromosuccinimide, HATU is 2-(7-azabenzotriazol)-N,N,N’,N’-tetramethylurea hexafluorophosphate, NCS is N-chlorosuccinimide, and Dess-Martin periodinane is (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one.

[0170] Compounds follow the general nomenclature in the art or are named using ChemDraw® software, and commercially available compounds are named using the supplier's catalog.

Embodiments for Carrying out the Invention

[0171] Hereinafter, the present invention will be described in detail by way of embodiments, which does not mean any limitation unfavorable to the present invention. The present invention is described in detail herein, and its specific embodiments are also disclosed. It will be apparent to those skilled in the art that various modifications and improvements to the specific embodiments of the present invention can be made without departing from the spirit and scope of the present invention.

[0172] Embodiment 1 [Chemistry] Step 1: Synthesis of Compound 1-2 Compound 1-1 (1 g, 1.31 mmol) and 1-1A (444.20 mg, 2.63 mmol) were weighed and dissolved in DMF (50 mL). DIPEA (1.70 g, 13.13 mmol, 2.29 mL) was added and the reaction was carried out at 100 °C for 2 hours. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), washed with water (30 mL), and concentrated. Compound 1-2 was obtained with MS m / z = 781.5 [M+H] + and obtained.

[0173] Step 2: Synthesis of Compound 1-3 Compound 1-2 (1.06 g, 1.36 mmol) was weighed and dissolved in DCM (30 mL). m-CPBA (276.34 mg, 1.36 mmol, purity 85%) was added at 0 °C and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated to obtain Compound 1-3 with MS m / z = 797.5 [M+H] + and obtained.

[0174] Step 3: Synthesis of Compound 1-4 Compound 1-2A (847.12 mg, 5.32 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (511.38 mg, 5.32 mmol) was added and the reaction was carried out at 0 °C for 30 minutes. Compound 1-3 (1.06 g, 1.33 mmol) was added and the reaction was carried out at 25 °C for 1 hour. 20 mL of saturated ammonium chloride solution was added to the reaction solution. The reaction solution was extracted with ethyl acetate (20 mL × 2), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Compound 1-4. MS m / z = 892.6 [M+H] + .

[0175] Step 4: Synthesis of Hydrochlorides of Compounds 1A and 1B Compound 1-4 (0.7 g, 784.82 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and the reaction was carried out at 25 °C for 2 hours. After the reaction, the reaction solution was directly concentrated. The hydrochloride salts of Compound 1A and Compound 1B were obtained by HPLC (Phenomenex C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 10~30%). Analytical method: chromatography column: ChromCore 120 C18 3 μm, 3.0×30 mm, mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)], gradient: acetonitrile (0.02% trifluoroacetic acid) %: 10~80%, 7 minutes_220&254 nm, retention time: 1A (Rt = 2.694 minutes), MS m / z = 652.3 [M+H] + , 1B (Rt = 2.848 minutes), MS m / z = 652.2 [M+H] + .

[0176] 1A: 1 H NMR (400 MHz, CD3OD) δ 6.90 - 6.66 (m, 1H), 5.75 - 5.45 (m, 1H), 5.39 - 5.22 (m, 1H), 5.00 - 4.94 (m, 2H), 4.79 - 4.63 (m, 3H), 4.24 - 4.07 (m, 1H), 4.02 - 3.81 (m, 3H), 3.71 - 3.62 (m, 1H), 3.61 - 3.54 (m, 1H), 3.51 - 3.44 (m, 1H), 3.42 - 3.35 (m, 1H), 3.17 - 3.04 (m, 1H), 2.71 - 2.46 (m, 3H), 2.27 - 2.17 (m, 1H), 2.23 (dt, J = 4.1, 13.1 Hz, 6H), 2.10 - 1.99 (m, 1H), 1.96 - 1.78 (m, 2H).

[0177] 1B: 11H NMR (400 MHz, CD3OD) δ 7.43 - 7.34 (m, 1H), 7.06 - 6.90 (m, 1H), 6.88 - 6.76 (m, 1H), 5.74 - 5.50 (m, 1H), 5.35 - 5.20 (m, 1H), 5.02 - 4.96 (m, 1H), 4.78 - 4.72 (m, 2H), 4.52 - 4.39 (m, 1H), 4.20 - 4.07 (m, 1H), 4.05 - 3.77 (m, 4H), 3.53 - 3.38 (m, 3H), 3.13 - 2.99 (m, 1H), 2.78 - 2.58 (m, 2H), 2.53 - 2.43 (m, 1H), 2.40 (br d, J = 3.8 Hz, 3H), 2.37 - 2.31 (m, 2H), 2.28 - 2.15 (m, 1H), 2.12 - 2.01 (m, 1H), 2.00 - 1.89 (m, 2H).

[0178] Embodiment 2 [Chemical formula] Step 1: Synthesis of Compound 2-1 Compound 1-1 (800 mg, 1.05 mmol) and 2-1A (175.18 mg, 1.16 mmol) were weighed and DMF (10 mL) was added. DIPEA (407.21 mg, 3.15 mmol, 548.80 μL) was added and the reaction was carried out at 100 °C for 2 hours. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), washed with water (30 mL), concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 2-1, MS m / z = 727.3 [M+H] + as obtained.

[0179] Step 2: Synthesis of Compound 2-2 Compound 2-1 (620 mg, 853.03 μmol) was weighed and dissolved in DCM (20 mL). m-CPBA (173.18 mg, 853.03 μmol, purity 85%) was added and reacted at 25 °C for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 2-2, MS m / z = 743.3 [M+H] + and obtained.

[0180] Step 3: Synthesis of Compound 2-3 Compound 1-2A (128.59 mg, 807.73 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium tert-butoxide (77.62 mg, 807.73 μmol) was added and reacted at 25 °C for 30 minutes. Compound 2-2 (300 mg, 403.87 μmol) was added and reacted at 25 °C for 1 hour. The reaction solution was diluted with 60 mL of ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 2-3. MS m / z = 838.4 [M+H] + .

[0181] Step 4: Synthesis of the hydrochloride salt of Compound 2 Compound 2-3 (0.3 g, 358.03 μmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added and reacted at 25 °C for 2 hours. After the reaction, the reaction solution was directly concentrated. The hydrochloride salt of Compound 2 was obtained by HPLC (Phenomenex C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 5~35%, 10 minutes). MS m / z = 598.4 [M+H] + . 11H NMR (400 MHz, CD3OD) δ ppm 6.85 - 6.67 (m, 1H), 5.69 - 5.52 (m, 1H), 5.32 - 5.22 (m, 1H), 5.00 - 4.94 (m, 1H), 4.80 - 4.74 (m, 3H), 4.61 - 4.34 (m, 1H), 4.06 - 3.83 (m, 4H), 3.55 - 3.36 (m, 3H), 3.25 - 3.10 (m, 1H), 3.07 - 2.95 (m, 1H), 2.82 - 2.61 (m, 2H), 2.54 - 2.44 (m, 1H), 2.42 - 2.30 (m, 5H), 2.30 - 2.17 (m, 1H), 2.14 - 1.98 (m, 1H), 1.89 - 1.65 (m, 3H), 1.34 - 1.25 (m, 3H).

[0182] Embodiment 3 [Chemical formula] Step 1: Synthesis of Compound 3-1 Compound 1-1 (300 mg, 0.39 mmol) and 3-1A (144.57 mg, 0.59 mmol) were weighed, and DMF (5 mL) was added. DIPEA (152.70 mg, 1.18 mmol, 205.80 μL) was added, and the reaction was carried out at 100 °C for 1 hour. The reaction solution was directly concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to obtain Compound 3-1 with MS m / z = 820.5 [M+H] + as obtained.

[0183] Step 2: Synthesis of Compound 3-2 Compound 3-1 (320 mg, 390.29 μmol) was weighed and dissolved in DCM (5 mL). m-CPBA (79.24 mg, 390.29 μmol, purity 85%) was added and the reaction was carried out at 25 °C for 0.5 h. The reaction solution was diluted with 40 mL of dichloromethane, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 3-2, MS m / z = 836.5 [M+H] + and obtained.

[0184] Step 3: Synthesis of Compound 3-3 Compound 1-2A (91.42 mg, 574.23 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (55.19 mg, 574.23 μmol) was added and the reaction was carried out at 25 °C for 30 min. Compound 3-2 (300 mg, 358.89 μmol) was added and the reaction was carried out at 25 °C for 1 h. The reaction solution was diluted with 40 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain Compound 3-3. MS m / z = 931.7 [M+H] + .

[0185] Step 4: Synthesis of the hydrochloride salt of Compound 3 Compound 3-3 (310 mg, 332.97 μmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added, and the mixture was reacted at 25 °C for 1 hour. After the reaction, the reaction solution was concentrated. The hydrochloride salt of Compound 3 was obtained by high performance liquid chromatography (HPLC) (Phenomenex C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 13 - 43%, 10 minutes). MS m / z = 691.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 7.08 - 6.91 (m, 1H), 6.87 - 6.71 (m, 1H), 5.77 - 5.47 (m, 1H), 5.35 - 5.15 (m, 2H), 4.99 (brs, 3H), 4.89 - 4.81 (m, 1H), 4.78 - 4.69 (m, 1H), 4.67 - 4.55 (m, 1H), 4.53 - 4.43 (m, 1H), 4.21 - 4.05 (m, 2H), 4.03 - 3.80 (m, 3H), 3.53 - 3.34 (m, 5H), 3.20 - 2.99 (m, 4H), 2.80 - 2.61 (m, 2H), 2.60 - 2.51 (m, 1H), 2.50 - 2.17 (m, 8H).

[0186] Embodiment 4

Chemical Structure

[0187] Step 2: Synthesis of Compound 4-3 Weighed 2,2,6,6-tetramethylpiperidine (220.59 g, 1.56 mol, 265.13 mL), and added THF (3,000 mL). Added n-butyllithium (2.5 M, 499.73 mL) at -5 °C, stirred for 0.5 h, and cooled to -60 °C. Added Compound 4-2 (280 g, 624.67 mmol), and stirred for 0.5 h. Finally, added DMF (228.28 g, 3.12 mol, 240.30 mL). Continued the reaction for 0.5 h. Quenched the reaction solution by pouring it into water (1,000 mL), adjusted the pH to 7 with hydrochloric acid, extracted with ethyl acetate (1,000 mL × 3), concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 4-3.

[0188] Step 3: Synthesis of Compound 4-4 Weighed Compound 4-3 (370 g, 807.30 mmol). Added toluene (1,500 mL), dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (2.86 g, 4.04 mmol, 2.86 mL), and tri-butyl(1-propynyl)tin (265.69 g, 807.30 mmol), and reacted at 120 °C for 2 h under nitrogen protection. Concentrated the reaction solution under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Compound 4-4. MS m / z = 418.1 [M+H] + 。

[0189] Step 4: Synthesis of Compound 4-5 Weighed Compound 4-4 (450 g, 970.13 mmol), and added DMF (100 mL). Added N-bromosuccinimide (189.93 g, 1.07 mol), and reacted at 25 °C for 2 h. Added additional N-bromosuccinimide (17.27 g, 97.01 mmol), and continued the reaction for 3 h. Centrifuged and dried the reaction solution directly, and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Compound 4-5. MS m / z = 496.0 [M+H] +。

[0190] Step 5: Synthesis of Compound 4-6 Compound 4-5 (55 g, 110.81 mmol) was weighed and DMF (300 mL) was added. Methyl fluorosulfonyldifluoroacetate (42.57 g, 221.61 mmol, 28.19 mL) and cuprous iodide (42.21 g, 221.61 mmol) were added, and the reaction was carried out at 110 °C for 2 hours under nitrogen protection. The reaction solution was quenched with 500 mL of water and extracted with ethyl acetate (600 mL × 3). The extracted organic phases were combined, washed successively with water (800 mL × 2) and saturated brine (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 4-6. MS m / z = 485.9 [M+H] + 。

[0191] Step 6: Synthesis of Compound 4-7 At 0 °C, methyl acetoacetate (18.42 g, 158.61 mmol, 17.10 mL) was added dropwise to a solution of sodium hydride (6.34 g, 158.61 mmol, purity 60%) in tetrahydrofuran (350 mL), and the reaction was carried out for 15 minutes. The reaction solution was cooled to -20 °C. Then, n-butyllithium (2.5 M, 63.44 mL) was added dropwise, and the mixture was stirred for 15 minutes after the addition. Then, a solution of Compound 4-6 (35 g, 72.10 mmol) in tetrahydrofuran (350 mL) was added, and the reaction was carried out for 0.5 hour. The reaction solution was quenched with 200 mL of saturated ammonium chloride solution and extracted with ethyl acetate (300 mL × 2). The extracted organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was separated by column chromatography (petroleum ether:ethyl acetate = 10:1~1:1) to obtain Compound 4-7. MS m / z = 624.2 [M+Na] + 。

[0192] Step 7: Synthesis of Compound 4-8 Compound 4-7 (38 g, 63.17 mmol) was weighed and dichloromethane (300 mL) was added. Then, N,N-dimethylformamide dimethyl acetal (9.03 g, 75.80 mmol) was added and the reaction was carried out at 25 °C for 16 hours. The reaction solution was cooled to 0 °C. Boron trifluoride etherate (10.76 g, 75.80 mmol, 9.32 mL) was added. The system was stirred at 0 °C for 1 hour. 200 mL of saturated sodium bicarbonate solution was added to the system. The organic phase was separated. The aqueous phase was extracted with 200 mL of dichloromethane. The extracted organic phases were mixed, washed with 250 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was separated by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 4-8. MS m / z = 612.1 [M+H] + .

[0193] Step 8: Synthesis of compound 4-9 Compound 4-8 (30 g, 49.05 mmol) was weighed and tetrahydrofuran (300 mL) was added. Lithium tributylborohydride (1 M, 53.96 mL) was added at -60 °C and the reaction was carried out at -60 °C for 1 hour. The reaction was quenched with 200 mL of water to the system. The reaction solution was extracted with ethyl acetate (300 mL × 2). The extracted organic phases were mixed, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was separated by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound 4-9. MS m / z = 614.1 [M+H] + .

[0194] Step 9: Synthesis of compound 4-10 Compound 4-9 (20 g, 32.59 mmol) was weighed and ethanol (200 mL) was added. Then, 2-methyl-2-thiourea sulfate (27.22 g, 97.78 mmol) and sodium carbonate (6.91 g, 65.19 mmol) were added, and the mixture was reacted at 50 °C for 13 hours. The reaction solution was concentrated, and 40 mL of water was added. The reaction solution was extracted with ethyl acetate (50 mL × 2). The extracted organic phases were combined, washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 4-10. MS m / z = 654.3 [M+H] + .

[0195] Step 10: Synthesis of Compound 4-11 Compound 4-10 (21 g, 32.13 mmol) was weighed and DMF (200 mL) was added. Then, N,N-diisopropylethylamine (12.46 g, 96.38 mmol, 16.79 mL) and N-phenylbis(trifluoromethanesulfonyl)imide (13.77 g, 38.55 mmol) were added, and the mixture was reacted at 25 °C for 1 hour. 300 mL of water was added to the system. The reaction solution was extracted with ethyl acetate (300 mL × 3), washed successively with water (400 mL × 2) and saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 4-11.

[0196] Step 11: Synthesis of Compound 4-12 Compound 4-11 (5 g, 6.36 mmol) and 3-1A (2.34 g, 9.55 mmol) were weighed and DMF (15 mL) was added. DIPEA (2.47 g, 19.09 mmol, 3.33 mL) was added, and the mixture was reacted at 100 °C for 1 hour. The reaction solution was directly concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 4-12 with MS m / z = 844.3 [M+H] + thus obtained.

[0197] Step 12: Synthesis of Compound 4-13 Compound 4-12 (5.3 g, 6.28 mmol) was weighed and dissolved in DCM (60 mL). m-CPBA (1.27 g, 6.28 mmol, purity 85%) was added and reacted at 25 °C for 0.5 h. The reaction solution was diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 4-13, MS m / z = 860.5 [M+H] + and obtained.

[0198] Step 13: Synthesis of Compound 4-14 Compound 1-2A (1.30 g, 8.16 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Sodium tert-butoxide (784.51 mg, 8.16 mmol) was added and reacted at 25 °C for 30 min. Compound 4-13 (5.4 g, 6.28 mmol) was added and reacted at 25 °C for 0.5 h. The reaction solution was diluted with 300 mL of ethyl acetate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 4-14. MS m / z = 955.8 [M+H] + .

[0199] Step 14: Synthesis of Compounds 4A and 4B Compound 4-14 (3.4 g, 3.56 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added, and the mixture was reacted at 20 °C for 1 hour. The reaction solution was concentrated, adjusted to pH 9 - 11 with saturated sodium carbonate solution, and extracted with dichloromethane (100 mL × 2). The extracted organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 4. SFC separation (chromatography column: DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 μm), mobile phase: [supercritical CO2 - methanol (0.1% ammonia)], methanol (0.1% ammonia)%: 40 - 40%) was carried out to obtain Compound 4A and Compound 4B. Chiral SFC analysis (chromatography column: DAICEL CHIRALCEL OD-3 (150 mm × 4.6 mm, 3 μm), mobile phase: [supercritical CO2 - methanol (0.05% diethylamine)], (methanol (0.05% diethylamine))%: 40 - 40%) was carried out. For Compound 4A, Rt = 3.084 minutes, ee value 99%. For Compound 4B, Rt = 5.110 minutes, ee value 98%.

[0200] Compound 4A: MS m / z = 715.4 [M+H] + , 11H NMR (400 MHz, CD3OD) δ ppm 6.98 - 6.86 (m, 1H), 6.73 - 6.58 (m, 1H), 5.40 - 5.21 (m, 1H), 5.20 - 5.12 (m, 1H), 4.84 (brs, 4H), 4.58 - 4.40 (m, 2H), 4.15 - 4.04 (m, 2H), 4.00 - 3.82 (m, 2H), 3.34 (s, 6H), 3.37 - 3.17 (m, 1H), 3.12 - 3.06 (m, 3H), 3.06 - 2.98 (m, 1H), 2.90 - 2.80 (m, 1H), 2.35 - 2.21 (m, 2H), 2.20 - 2.06 (m, 3H), 2.05 - 2.02 (m, 3H), 2.01 - 1.84 (m, 3H). Compound 4B: MS m / z = 715.4 [M+H] + .

[0201] Embodiment 5 [Chemical formula] Step 1: Synthesis of Intermediate 5-1A SFC analysis of Compound 5-1 (chromatography column: Chiralpak IH-3, 100×4.6 mm I.D., 3 μm, mobile phase: A (supercritical CO2) and B (EtOH containing 0.1% isopropylamine), gradient: B% = 10 - 50%, run time 3.7 minutes) was carried out. Peak times: 1.266 minutes and 1.521 minutes, where Compound 5-1A was at 1.521 minutes. Then, purification by supercritical fluid chromatography (SFC) (chromatography column: ChiralPak IH, 250×50 mm, 10 μm, mobile phase: [supercritical CO2 - ethanol (0.1% ammonia)], ethanol (0.1% ammonia)%: 20 - 20%) was carried out to obtain Compound 5-1A. SFC analysis (chromatography column: Chiralpak IH-3, 100×4.6 mm I.D., 3 μm, mobile phase: A (supercritical CO2) and B (EtOH containing 0.1% isopropylamine), gradient: B% = 10 - 50%, 4 minutes, flow rate: 3.4 mL / min, wavelength: 220 nm, pressure: 2000 psi). Compound 5-1A, Rt = 1.489 minutes, ee value 98.8%. 1 H NMR (400 MHz, CDCl3) δ = 4.99 - 4.86 (m, 2H), 4.26 - 3.95 (m, 3H), 3.59 (m, 1H), 3.01 - 2.88 (m, 1H), 2.88 - 2.15 (m, 4H), 1.91 (s, 1H), 1.20 - 1.09 (m, 3H).

[0202] Step 2: Synthesis of Intermediate 5-2 Lithium aluminum hydride (1.55 g, 40.15 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and cooled to 0°C. Under nitrogen protection, a solution of Compound 5-1A (2.8 g, 13.38 mmol) in anhydrous tetrahydrofuran (20 mL) was added and reacted at 70°C for 1 hour. At 0°C, 1.5 mL of water was added to the reaction solution. 1.5 mL of 15% sodium hydroxide solution was added. Then, 4.5 mL of water was added and stirred for 20 minutes. The reaction solution was filtered. The filter cake was washed with 10 mL of tetrahydrofuran, and the filtrate was concentrated to obtain Compound 5-2. 11H NMR (400 MHz, CDCl3) δ = 4.99 - 4.86 (m, 2H), 4.28 - 3.95 (m, 3H), 3.61 - 3.59 (m, 1H), 3.00 - 2.88 (m, 1H), 2.74 - 2.27 (m, 4H), 1.91 (s, 1H), 1.20 - 1.08 (m, 3H).

[0203] Step 3: Synthesis of Compound 5-3 Compound 5-2 (88.20 mg, 575.63 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (55.32 mg, 575.63 μmol) was added and the reaction was carried out at 25 °C for 30 minutes. Compound 4-13 (330 mg, 383.75 μmol) was added and the reaction was carried out at 25 °C for 0.5 hour. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 5-3. MS m / z = 949.1 [M+H] + .

[0204] Step 4: Synthesis of Compounds 5A and 5B Compound 5-3 (360 mg, 379.33 μmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated and separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 10 - 40%, 10 minutes) to obtain the hydrochloride salt of Compound 5. SFC separation (chromatography column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm), mobile phase: [supercritical CO2-ethanol (0.1% ammonia)], ethanol (0.1% ammonia) %: 40 - 40%) was carried out to obtain Compounds 5A and 5B. Chiral SFC analysis (chromatography column: DAICEL CHIRALCEL OD-3 (150 mm×4.6 mm, 3 μm), mobile phase: [supercritical CO2-ethanol (0.05% diethylamine)], ethanol (0.05% diethylamine) %: 40 - 40%) was carried out. Compound 5A, Rt = 0.848 minutes, ee value 100%. Compound 5B, Rt = 2.371 minutes, ee value 99%.

[0205] Compound 5A: MS m / z = 709.3 [M+H] + , 1 1H NMR (400 MHz, CD3Cl) δ ppm 6.93 - 6.85 (m, 1H), 6.84 - 6.77 (m, 1H), 5.36 - 5.22 (m, 2H), 5.20 - 5.11 (m, 1H), 4.89 - 4.41 (m, 10H), 4.18 - 3.99 (m, 3H), 3.97 - 3.77 (m, 2H), 3.61 - 3.48 (m, 1H), 3.42 - 3.26 (m, 4H), 3.17 - 3.04 (m, 4H), 3.01 - 2.88 (m, 2H), 2.73 - 2.61 (m, 1H), 2.56 - 2.42 (m, 1H), 2.35 - 2.23 (m, 2H), 2.21 - 2.12 (m, 2H), 2.10 - 2.04 (m, 3H). Compound 5B: MS m / z = 709.3 [M+H] + .

[0206] Embodiment 6

Chemical formula

Chemical formula

[0207] Step 2: Synthesis of Intermediate 6-3 The crude product 6-2 (20 g) was dissolved in DMF (65 mL), potassium carbonate (14.2 g, 102 mmol) was added, and the reaction was carried out at 25°C for 12 hours. The reaction solution was diluted with 500 mL of ethyl acetate, washed with water (300 mL × 2), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 6-3.

[0208] Step 3: Synthesis of Intermediate 6-4 Compound 6-3 (7 g, 32.23 mmol) was dissolved in 2-methyltetrahydrofuran (75 mL). After three nitrogen replacements, under nitrogen protection at 10°C, red aluminum (37.2 g, 129 mmol, 35.8 mL, purity 70%) was slowly added and reacted at 25°C for 12 hours. The reaction solution was quenched by dropping a 26.0% aqueous sodium tartrate solution and extracted with 2-methyltetrahydrofuran (200 mL). The aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL × 3). The organic phases were mixed, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6-4.

[0209] Step 4: Synthesis of Intermediate 6-5 Compound 6-4 (2.2 g, 13 mmol) was dissolved in DCM (30 mL). Imidazole (3.5 g, 53 mmol), 4-dimethylaminopyridine (160 mg, 1.3 mmol), and tert-butyldiphenylchlorosilane (7.2 g, 25 mmol) were added, and the reaction was carried out at 45 °C for 12 hours. Water (50 mL) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (40 mL). The organic phases were combined, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Methyl tert-butyl ether (10 mL), n-heptane (21 mL), and hydrochloric acid solution (2 M, 21 mL) were added. The aqueous phase was separated, washed with a mixed solvent of methyl tert-butyl ether and n-heptane (1:2) (20 mL × 3), adjusted to pH 7 with an aqueous sodium carbonate solution, and extracted with 200 mL of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 10:1), and the first point (R f = 0.6, the other isomer: R f = 0.5) was separated to obtain crude intermediate 6-5.

[0210] Step 5: Synthesis of intermediate 6-6 SFC analysis of compound 6-5 (2 g, 4.6 mmol) (chromatography column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm, mobile phases: A (supercritical CO2) and B (methanol containing 0.05% diethylamine), gradient: B% = 5 - 10%, flow rate: 3 mL / min) was carried out. Peak times: 2.117 min and 2.980 min, where intermediate 6-6 was at 2.117 min. For separation and purification, chiral SFC separation (chromatography column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm), mobile phase: [supercritical CO2 - methanol (0.1% ammonia)], methanol (0.1% ammonia)%: 25 - 25%, 4.5 min) was carried out to obtain compound 6-6. SFC analysis method (chromatography column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm, mobile phases: A (supercritical CO2) and B (methanol containing 0.05% diethylamine), gradient: B% = 5 - 10%, flow rate: 3 mL / min), Rt = 2.014 min, ee value 98%. MS m / z = 410.3 [M+H] + .

[0211] Step 6: Synthesis of intermediate 6-7 Compound 6-6 (1.2 g, 2.93 mmol) was dissolved in 24 mL of 1,4-dioxane, concentrated hydrochloric acid (12 M, 7.20 mL) was added, and the mixture was reacted at 95 °C for 12 h. The reaction solution was cooled, diluted with 10 mL of water, and washed with 10 mL of ethyl acetate. The aqueous phase was freeze-dried to obtain the hydrochloride salt of compound 6-7. The hydrochloride salt was dissolved in methanol (20 mL). 2 g of potassium carbonate was added. The reaction solution was filtered, concentrated, then dissolved in tetrahydrofuran (20 mL), filtered, and concentrated to obtain compound 6-7.

[0212] Step 7: Synthesis of compound 6-8 Compound 6-7 (92.58 mg, 540.74 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (51.97 mg, 540.74 μmol) was added and the reaction was carried out at 25 °C for 30 minutes. Compound 4-13 (310 mg, 360.49 μmol) was added and the reaction was carried out at 25 °C for 0.5 hour. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 6-8. MS m / z = 967.3 [M+H] + .

[0213] Step 8: Synthesis of Compounds 6A and 6B Compound 6-8 (345 mg, 356.76 μmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated and separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile%: 10~40%, 10 minutes) to obtain the hydrochloride salt of Compound 6. SFC separation (chromatography column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm), mobile phase: [supercritical CO2-methanol (0.1% ammonia)], methanol (0.1% ammonia)%: 40~40%) was carried out to obtain Compounds 6A and 6B. Chiral SFC analysis (chromatography column: DAICEL CHIRALCEL OD-3 (150 mm×4.6 mm, 3 μm), mobile phase: [supercritical CO2-methanol (0.05% diethylamine)], methanol (0.05% diethylamine)%: 40~40%) was carried out. For Compound 6A, Rt = 3.658 minutes, ee value 99.9%. For Compound 6B, Rt = 7.041 minutes, ee value 99.9%.

[0214] Compound 6A: MS m / z = 727.3 [M+H] + , 11H NMR (400 MHz, CD3OD) δ ppm 6.90 - 6.64 (m, 2H), 6.60 - 6.55 (m, 1H), 5.13 - 5.01 (m, 1H), 4.84 (brs, 2H), 4.69 - 4.57 (m, 2H), 4.47 - 4.38 (m, 2H), 4.37 - 4.26 (m, 3H), 4.06 - 3.96 (m, 1H), 3.90 - 3.75 (m, 2H), 3.72 - 3.62 (m, 1H), 3.26 - 3.23 (m, 3H), 3.19 - 3.10 (m, 2H), 3.04 - 2.93 (m, 3H), 2.88 - 2.62 (m, 3H), 2.36 - 2.23 (m, 1H), 2.02 (s, 5H), 1.93 - 1.87 (m, 3H). Compound 6B: MS m / z = 727.3 [M+H] + .

[0215] Embodiment 7 [Chemical formula] Step 1: Synthesis of Intermediate 4-11B The SFC separation of Compound 4-11 (chromatography column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 μm), mobile phase: [supercritical CO2 - ethanol (0.1% ammonia)], ethanol (0.1% ammonia)%: 25 - 25%) was carried out to obtain Compound 4-11B and its isomer. Chiral SFC analysis (chromatography column: ChiralPak IG-3 (100 mm × 4.6 mm, 3 μm), mobile phase: [supercritical CO2 - ethanol (0.05% diethylamine)], (ethanol (0.05% diethylamine))%: 5 - 40%) was carried out. For Compound 4-11B, Rt = 3.055 min, ee value 99%. For the isomer, Rt = 2.574 min, ee value 99%.

[0216] Step 2: Synthesis of Intermediate 7-2 Compound 4-11B (0.4 g, 509.07 μmol) was weighed and dissolved in DMF (15 mL). Compound 7-1 (125.62 mg, 610.88 μmol) was weighed and added. Then, DIPEA (197.38 mg, 1.53 mmol) was added to the reaction system, and the mixture was reacted at 100 °C for 1 hour. Water (15 mL) was added to the reaction solution. The reaction solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Compound 7-2, MS m / z = 805.6 [M+H] + and obtained.

[0217] Step 3: Synthesis of Intermediate 7-3 Compound 7-2 (381.80 mg, 474.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (96.31 mg, 474.37 μmol, purity 85%) was added, and the mixture was reacted at 25 °C for 1 hour. Water (15 mL) was added to the reaction solution. The reaction solution was diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 7-3, MS m / z = 821.6 [M+H] + and obtained.

[0218] Step 4: Synthesis of Intermediate 7-4 Compound 5-2 (286.64 mg, 1.87 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (179.79 mg, 1.87 mmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 7-3 (383.90 mg, 467.69 μmol) was added, and the mixture was reacted at 0 °C for 1 hour. Water (15 mL) was added to the reaction solution. The reaction solution was diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 7-4. MS m / z = 910.5 [M+H] + .

[0219] Step 5: Synthesis of Compounds 7A and 7B Compound 7-4 (0.2833 g, 311.33 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (4.33 g, 38.01 mmol, 2.82 mL) was added and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated, adjusted to pH 10 with saturated sodium carbonate solution, and extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia)-acetonitrile], acetonitrile %: 41 - 71% over 8 minutes) to obtain Compound 7A and Compound 7B. Chiral SFC analysis (chromatography column: DAICEL CHIRALCEL AS-3 (100 mm×4.6 mm, 3 μm), mobile phase: [supercritical CO2-methanol (0.05% diethylamine)], (methanol (0.05% diethylamine)) %: 40 - 40%). Compound 7A, Rt = 1.445 minutes, ee value 97.4%, MS m / z = 670.3 [M+H] + Compound 7B, Rt = 0.863 minutes, ee value 94.9%, MS m / z = 670.3 [M+H] + .

[0220] Embodiment 8

Chemical formula

[0221] Step 2: Synthesis of hydrochloride salt of intermediate 8-3 Compound 8-2 (209 mg, 674.54 μmol) was weighed. 4M hydrochloric acid / ethyl acetate solution (5 mL) was added. The reaction system was reacted at room temperature (18 °C) for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of Compound 8-3, MS m / z = 195.1 [M+H] + and obtained as follows.

[0222] Step 3: Synthesis of intermediate 8-4 Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (8 mL). The hydrochloride salt of Compound 8-3 (59.33 mg) was added. DIPEA (98.69 mg, 763.60 μmol) was weighed and added to the reaction system, and the reaction was carried out at 100 °C for 1 hour. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 8-4, MS m / z = 830.6 [M+H] + and obtained as follows.

[0223] Step 4: Synthesis of intermediate 8-5 Compound 8-4 (0.099 g, 119.29 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (24.22 mg, 119.29 μmol, purity 85%) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 8-5, MS m / z = 846.6 [M+H] + and obtained.

[0224] Step 5: Synthesis of Intermediate 8-6 Compound 5-2 (46.73 mg, 305.00 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium tert-butoxide (29.31 mg, 305.00 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 8-5 (129 mg, 152.50 μmol) was added, and the reaction was carried out at 0 °C for 1 hour. Water (20 mL) was added to the reaction solution. The reaction solution was diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 8-6. MS m / z = 935.5 [M+H] + .

[0225] Step 6: Synthesis of the hydrochloride salt of Compound 8 Compound 8-6 (0.142 g, 151.87 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (2.11 g, 18.54 mmol, 1.38 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 10 - 40%, 10 minutes) to obtain the hydrochloride salt of Compound 8. MS m / z = 695.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ = 6.96 (d, J = 8.5 Hz, 1H), 6.69 - 6.47 (m, 1H), 5.39 - 5.32 (m, 2H), 5.30 - 5.21 (m, 1H), 5.13 - 5.04 (m, 2H), 4.95 (br d, J = 5.0 Hz, 2H), 4.69 - 4.56 (m, 2H), 4.55 - 4.42 (m, 2H), 4.41 - 4.31 (m, 2H), 4.06 - 3.98 (m, 1H), 3.98 - 3.91 (m, 1H), 3.87 - 3.77 (m, 1H), 3.47 - 3.36 (m, 3H), 3.30 - 3.22 (m, 2H), 3.20 - 2.98 (m, 5H), 2.91 - 2.81 (m, 1H), 2.51 - 2.40 (m, 1H), 2.33 - 2.12 (m, 3H), 2.04 (s, 3H).

[0226] Embodiment 9 [Chemical Structure] Step 1: Synthesis of Intermediate 9-2 Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (15 mL). Compound 9-1 (61.59 mg, 305.44 μmol) was added. Then, DIPEA (98.69 mg, 763.60 μmol, 133.00 μL) was added and the reaction was carried out at 100 °C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 9-2, MS m / z = 801.6 [M+H] + and obtained.

[0227] Step 2: Synthesis of Intermediate 9-3 Compound 9-2 (158.80 mg, 198.29 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (40.26 mg, 198.29 μmol, purity 85%) was added and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 9-3, MS m / z = 817.4 [M+H] + and obtained.

[0228] Step 3: Synthesis of Intermediate 9-4 Compound 5-2 (60.44 mg, 394.44 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium tert-butoxide (37.91 mg, 394.44 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 9-3 (0.1611 g, 197.22 μmol) was added and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 9-4. MS m / z = 906.7 [M+H] + .

[0229] Step 4: Synthesis of the hydrochloride salt of Compound 9 Compound 9-4 (127.44 mg, 140.66 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (1.96 g, 17.17 mmol, 1.28 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 20 - 50%, 10 minutes) to obtain the hydrochloride salt of Compound 9. MS m / z = 666.3 [M+H] + 。

[0230] Embodiment 10

Chemical formula

[0231] Step 2: Synthesis of Intermediate 10-3 Compound 10-2 (0.202 g, 260.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (52.86 mg, 260.37 μmol, purity 85%) was added, and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and Compound 10-3 was obtained with MS m / z = 792.5 [M+H] + and obtained

[0232] Step 3: Synthesis of Intermediate 10-4 Compound 5-2 (79.34 mg, 517.80 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium tert-butoxide (49.76 mg, 517.80 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 10-3 (0.1611 g, 197.22 μmol) was added, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 10-4. MS m / z = 881.7 [M+H] + .

[0233] Step 4: Synthesis of the hydrochloride salt of Compound 10 Compound 10-4 (0.1338 g, 151.89 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (5 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 20 - 50%, 10 minutes) to obtain the hydrochloride salt of Compound 10. MS m / z = 641.1 [M+H] + .

[0234] Embodiment 11

Chemical formula

[0235] Step 2: Synthesis of Intermediate 11-3 Compound 11-2 (452.40 mg, 589.95 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (119.77 mg, 589.95 μmol, purity 85%) was added and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 11-3, MS m / z = 783.5 [M+H] + and obtained.

[0236] Step 3: Synthesis of Intermediate 11-4 Compound 5-2 (180.46 mg, 1.18 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butyl alcohol (113.19 mg, 1.18 mmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 11-3 (0.461 g, 588.88 μmol) was added and reacted at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 11-4. MS m / z = 872.5 [M+H] + .

[0237] Step 4: Synthesis of hydrochloride salts of Compound 11A and 11B Compound 11-4 (0.2 g, 229.37 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (3.19 g, 28.00 mmol, 2.08 mL) was added and reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile%: 20 - 50%, 10 minutes) to obtain the hydrochloride salts of Compound 11A and Compound 11B. Analytical method: chromatography column: ChromCore 120 C18 3μm, 3.0×30 mm, mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)], acetonitrile (0.02% trifluoroacetic acid)%: 10 - 80%, 7 minutes, retention time: 11A (Rt = 2.902 minutes), MS m / z = 632.2 [M+H] + , 11B (Rt = 3.020 minutes), MS m / z = 632.2 [M+H] + .

[0238] Embodiment 12 [Chemical formula] Step 1: Synthesis of Intermediate 12-2 Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (15 mL). Compound 12-1 (54.27 mg, 305.44 μmol) was added. Then, DIPEA (98.69 mg, 763.60 μmol, 133.00 μL) was added, and the mixture was reacted at 100 °C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 12-2, MS m / z = 777.4 [M+H] + and obtained.

[0239] Step 2: Synthesis of Intermediate 12-3 Compound 12-2 (0.1976 g, 254.35 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (51.67 mg, 254.35 μmol, purity 85%) was added, and the mixture was reacted at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 12-3, MS m / z = 793.6 [M+H] + and obtained.

[0240] Step 3: Synthesis of Intermediate 12-4 Compound 5-2 (77.68 mg, 507.01 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (48.73 mg, 507.01 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 12-3 (0.201 g, 253.51 μmol) was added, and the mixture was reacted at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 12-4. MS m / z = 882.5 [M+H] + .

[0241] Step 4: Synthesis of hydrochloride salt of Compound 12 Compound 12-4 (0.221 g, 250.57 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (3.49 g, 30.59 mmol, 2.27 mL) was added, and the mixture was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 20 - 50%, 10 minutes) to obtain the hydrochloride salt of Compound 12. MS m / z = 642.4 [M+H] + 。

[0242] Embodiment 13

Chemical formula

[0243] Step 2: Synthesis of Intermediate 13-3 Compound 13-2 (0.4165 g, 503.68 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (102.26 mg, 503.68 μmol, purity 85%) was added and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and Compound 13-3 was obtained with MS m / z = 843.5 [M+H] + and obtained

[0244] Step 3: Synthesis of Intermediate 13-4 Compound 5-2 (154.33 mg, 1.01 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (96.80 mg, 1.01 mmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 13-3 (0.4245 g, 503.61 μmol) was added and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 13-4. MS m / z = 932.4 [M+H] + .

[0245] Step 4: Synthesis of Hydrochlorides of Compounds 13A and 13B Compound 13-4 (0.293 g, 314.26 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (4.37 g, 38.36 mmol, 2.85 mL) was added, and the mixture was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile%: 20 - 50%, 10 minutes) to obtain hydrochlorides of compounds 13A and 13B. Analytical method: chromatography column: ChromCore 120 C18 3 μm, 3.0×30 mm, mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)], acetonitrile (0.02% trifluoroacetic acid)%: 10 - 80%, 7 minutes, retention time: 13A (Rt = 2.891 minutes), MS m / z = 692.2 [M+H] + , 13B (Rt = 3.126 minutes), MS m / z = 692.2 [M+H] + .

[0246] Embodiment 14

Chemical Structure

[0247] Step 2: Synthesis of Intermediate 14-3 Compound 14-2 (200.23 mg, 227.95 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (39.34 mg, 227.95 μmol, purity 85%) was added and reacted at room temperature (25 °C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain Compound 14-3 with MS m / z = 894.3 [M+H] + obtained at

[0248] Step 3: Synthesis of Intermediate 14-4 Compound 5-2 (61.67 mg, 402.52 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (38.68 mg, 402.52 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 14-3 (180 mg, 201.26 μmol) was added and reacted at 0 °C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH = 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 14-4. MS m / z = 983.8 [M+H] + .

[0249] Step 4: Synthesis of Compound 14 and the hydrochloride salt of Compound 14 Compound 14-4 (118 mg, 119.98 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia)-acetonitrile], acetonitrile %: 52 - 82% over 8 minutes) to obtain Compound 14. MS m / z = 743.2 [M+H] + .

[0250] The crude product was separated by HPLC under hydrochloric acid conditions (chromatography column: Xtimate C18 150×40mm×5μm, mobile phase: [water (0.05% HCl) - acetonitrile], acetonitrile%: 17 - 47%, 10 minutes) to obtain the hydrochloride salt of compound 14. Chiral SFC analysis (chromatography column: DAICEL CHIRALCEL OD-3 (50mm×4.6mm, 3μm), mobile phase: [supercritical CO2 - ethanol (0.05% diethylamine)], ethanol (0.05% diethylamine)%: 40 - 40%) was carried out. Rt = 0.745 minutes. MS m / z = 743.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ = 7.00 - 6.93 (m, 1H), 5.34 (br d, J = 5.9 Hz, 2H), 5.27 - 5.15 (m, 2H), 5.09 (br d, J = 14.0 Hz, 1H), 5.00 - 4.93 (m, 2H), 4.83 (br d, J = 11.8 Hz, 1H), 4.65 (br d, J = 11.9 Hz, 1H), 4.59 - 4.51 (m, 1H), 4.37 - 4.27 (m, 2H), 4.17 (br d, J = 13.4 Hz, 1H), 3.96 - 3.89 (m, 2H), 3.85 - 3.76 (m, 1H), 3.35 - 3.31 (m, 1H), 3.29 - 3.19 (m, 1H), 3.16 (s, 3H), 3.13 - 3.09 (m, 3H), 3.08 - 2.97 (m, 2H), 2.83 (br d, J = 16.3 Hz, 1H), 2.62 - 2.48 (m, 1H), 2.47 - 2.33 (m, 2H), 2.31 - 2.13 (m, 3H), 2.04 (s, 3H).

[0251] Embodiment 15

Chemical formula

[0252] Step 2: Synthesis of Intermediate 15-3 Compound 15-2 (150.00 mg, 178.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (30.78 mg, 178.37 μmol, purity 85%) was added and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 15-3, MS m / z = 857.6 [M+H] + and obtained.

[0253] Step 3: Synthesis of Intermediate 15-4 Compound 5-2 (46.49 mg, 303.41 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (29.16 mg, 303.41 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 15-3 (130 mg, 151.71 μmol) was added and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH = 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 15-4. MS m / z = 946.8 [M+H] + .

[0254] Step 4: Synthesis of the Hydrochloride Salt of Compound 15 Compound 15-4 (100 mg, 105.70 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl) - acetonitrile], acetonitrile %: 20 - 50%, 10 minutes) to obtain the hydrochloride salt of Compound 15. MS m / z = 706.3 [M+H] + 。

[0255] Embodiment 16

Chemical formula

[0256] Step 2: Synthesis of Intermediate 16-3 Triphenylphosphine (777.45 mg, 2.96 mmol) and elemental iodine (752.31 mg, 2.96 mmol) were weighed and dissolved in dichloromethane (10 mL) at 0 °C. After dissolution, DIPEA (766.17 mg, 5.93 mmol) was added. Then, a tetrahydrofuran solution (10 mL) of compound 16-2 (500 mg, 1.48 mmol) was added, and the mixture was stirred and reacted at 20 °C for 6 hours. The reaction solution was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-3. MS m / z = 320.2 [M+H] + 。

[0257] Step 3: Synthesis of hydrochloride of intermediate 16-4 Compound 16-3 (1 g, 1.41 mmol) was weighed and dissolved in 4M hydrochloric acid / ethyl acetate solution (10 mL), and stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of compound 16-4.

[0258] Step 4: Synthesis of intermediate 16-5 Compound 4-11B (200.00 mg, 254.53 μmol) was weighed and dissolved in DMF (10 mL). The hydrochloride of compound 16-4 (97.63 mg) was added. Then, DIPEA (148.03 mg, 1.15 mmol, 199.50 μL) was added and reacted at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-5 with MS m / z = 855.5 [M+H] + thus obtained.

[0259] Step 5: Synthesis of intermediate 16-6 Compound 16-5 (120 mg, 140.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (24.22 mg, 140.37 μmol, purity 85%) was added and reacted at room temperature (25 °C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain Compound 16-6, MS m / z = 871.4 [M+H] + obtained thereby.

[0260] Step 6: Synthesis of Intermediate 16-7 Compound 5-2 (35.19 mg, 229.64 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (22.07 mg, 229.64 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 16-6 (100 mg, 114.82 μmol) was added and reacted at 0 °C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH = 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 16-7. MS m / z = 960.8 [M+H] + 。

[0261] Step 7: Synthesis of Compound 16 Compound 16-7 (70 mg, 72.91 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia)-acetonitrile], acetonitrile %: 52 - 82% over 8 minutes) to obtain Compound 16. MS m / z = 720.2 [M+H] + 。

[0262] Embodiment 17

Chemical formula

[0263] Step 2: Synthesis of Intermediate 17-2 Compound 17-1 (400 mg, 1.33 mmol) was weighed and dissolved in acetonitrile (10 mL). DIPEA (517.39 mg, 4.00 mmol, 697.29 μL) and N-hydroxyacetamidine (118.63 mg, 1.60 mmol) were added, and the reaction was carried out at 150 °C for 0.5 hour under microwave irradiation. The reaction solution was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Compound 17-2. MS m / z = 320.2 [M+H] + 。

[0264] Step 3: Synthesis of the hydrochloride salt of Intermediate 17-3 Compound 17-2 (260 mg, 814.13 μmol) was weighed and dissolved in 4M hydrochloric acid / ethyl acetate solution (10 mL), and stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of Compound 17-3.

[0265] Step 4: Synthesis of Intermediate 17-4 Compound 4-11B (300 mg, 381.80 μmol) was weighed and dissolved in DMF (10 mL). The hydrochloride salt of Compound 17-3 (146.44 mg) was added. Then, DIPEA (148.03 mg, 1.15 mmol, 199.50 μL) was added, and the reaction was carried out at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 17-4, MS m / z = 855.4 [M+H] + and obtained.

[0266] Step 5: Synthesis of Intermediate 17-5 Compound 17-4 (150 mg, 175.46 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (30.28 mg, 175.46 μmol, purity 85%) was added, and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain Compound 17-5, MS m / z = 871.3 [M+H] + obtained as

[0267] Step 6: Synthesis of Intermediate 17-6 Compound 5-2 (52.78 mg, 344.47 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (33.10 mg, 344.47 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 17-5 (150.00 mg, 172.23 μmol) was added, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH = 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 17-6. MS m / z = 960.5 [M+H] + 。

[0268] Step 7: Synthesis of Compound 17 Compound 17-6 (130 mg, 135.41 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia)-acetonitrile], acetonitrile %: 52 - 82% over 8 minutes) to obtain Compound 17. MS m / z = 720.3 [M+H] + 。

[0269] Embodiment 18

Chemical Structure

[0270] Step 2: Synthesis of Intermediate 18-2 Compound 18-1 (106.5 mg, 141.84 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (28.80 mg, 141.84 μmol, purity 85%) was added and the mixture was reacted at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 18-2, MS m / z = 767.5 [M+H] + and obtained.

[0271] Step 3: Synthesis of Intermediate 18-3 Compound 5-2 (86.32 mg, 563.35 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (54.14 mg, 563.35 μmol) was added. The reaction system was reacted at 0 °C for 1 hour. Compound 18-2 (0.108 g, 140.84 μmol) was added and the mixture was reacted at 0 °C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 18-3. MS m / z = 856.7 [M+H]+ 。

[0272] Step 4: Synthesis of hydrochloride salt of Compound 18 Compound 18-3 (120.4 mg, 140.66 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1.96 g, 17.17 mmol, 1.28 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 10 - 40%, 10 minutes) to obtain the hydrochloride salt of Compound 18. MS m / z = 616.3 [M+H] + 。

[0273] Embodiment 19

Chemical formula

[0274] Step 2: Synthesis of Intermediate 19-3 Compound 19-2 (120 mg, 139.22 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (24.03 mg, 139.22 μmol, purity 85%) was added, and the reaction was carried out at room temperature (25 °C) for 0.5 h. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain Compound 19-3, MS m / z = 878.3 [M+H] + and obtained

[0275] Step 3: Synthesis of Intermediate 19-4 Compound 5-2 (41.89 mg, 273.37 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (26.27 mg, 273.37 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 h. 5 mL of a tetrahydrofuran solution of Compound 19-3 (120 mg, 136.69 μmol) was added, and the reaction was carried out at 0 °C for 1 h. The reaction solution was quenched with water (20 mL), adjusted to pH = about 6 with dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 19-4. MS m / z = 967.5 [M+H] + .

[0276] Step 4: Synthesis of Compound 19 Compound 19-4 (80 mg, 82.73 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (5 mL) was added, and the reaction was carried out at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile], acetonitrile %: 53~83%, 9 min) to obtain Compound 19. MS m / z = 727.2 [M+H] + .

[0277] Embodiment 20 [Chemical formula] Step 1: Synthesis of Intermediate 20-2 Compound 20-1 (400 mg, 1.30 mmol) was weighed and dissolved in DMF (10 mL). NBS (346.30 mg, 1.95 mmol) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was extracted with ethyl acetate (30 mL × 3), washed with water (30 mL × 3), and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 20-2. MS m / z = 387.0, 389.0 [M+H] + .

[0278] Step 2: Synthesis of the hydrochloride salt of Intermediate 20-3 Compound 20-2 (250 mg, 645.54 μmol) was weighed and dissolved in hydrogen chloride / ethyl acetate (4 M, 10 mL), and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of Compound 20-3. MS m / z = 287.0, 289.1 [M+H] + .

[0279] Step 3: Synthesis of Intermediate 20-4 Compound 4-11B (200 mg, 254.53 μmol) was weighed and dissolved in DMF (5 mL). The hydrochloride salt of Compound 20-3 (123.56 mg) was added. Then, DIPEA (98.69 mg, 763.60 μmol) was added, and the reaction was carried out at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 20-4 with MS m / z = 922.1, 924.0 [M+H] + and obtained.

[0280] Step 4: Synthesis of Intermediate 20-5 Compound 20-4 (180 mg, 195.05 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (33.66 mg, 195.05 μmol, purity 85%) was added, and the reaction was carried out at room temperature (25 °C) for 0.5 h. The reaction mixture was quenched with water (15 mL), diluted with 20 mL of dichloromethane, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain Compound 20-5, MS m / z = 938.2, 940.15 [M+H] + and obtained.

[0281] Step 5: Synthesis of Intermediate 20-6 Compound 5-2 (39.17 mg, 255.64 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium tert-butoxide (24.57 mg, 255.64 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 h. A 5 mL tetrahydrofuran solution of Compound 20-5 (120 mg, 127.82 μmol) was added, and the reaction was carried out at 0 °C for 1 h. The reaction mixture was quenched with water (20 mL), adjusted to pH = about 6 with dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 20-6. MS m / z = 1027.4, 1029.5 [M+H] + .

[0282] Step 6: Synthesis of Compound 20 Compound 20-6 (100 mg, 97.28 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile], acetonitrile %: 45-75%, 8 min) to obtain Compound 20. MS m / z = 787.1, 789.05 [M+H] + .

[0283] Embodiment 21

Chem.

[0284] Step 2: Synthesis of Hydrochloride Salt of Compound 21 Compound 21-1 (100 mg, 96.7 μmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (771.96 mg, 6.77 mmol) was added and reacted at 18 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [water (0.04% HCl)-acetonitrile], acetonitrile %: 15 - 45%, 8 minutes) to obtain the hydrochloride salt of Compound 21. MS m / z = 793.1, 795.1 [M+H] + 。

[0285] Embodiment 22

Chem.

[0286] Step 2: Synthesis of the hydrochloride salt of compound 22 Compound 22-1 (0.077 g, 77.82 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (1.08 g, 9.50 mmol) was added, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 20 - 50%, 10 minutes) to obtain the hydrochloride salt of compound 22. MS m / z = 749.2 [M+H] + .

[0287] Embodiment 23 [Chemical formula] Step 1: Synthesis of intermediate 23-1 Compound 1-2A (15.41 mg, 96.82 μmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL) and cooled to -15 °C under nitrogen protection. Sodium tert-butoxide (7.44 mg, 77.46 μmol) was added and reacted at -15 °C for 0.25 h. A tetrahydrofuran solution (0.5 mL) of compound 19-3 (17 mg, 19.36 μmol) was added dropwise and reacted at -15 °C for 1 h. The reaction mixture was quenched with 3 mL of saturated ammonium chloride and extracted with ethyl acetate (2 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-1. MS m / z = 973.2 [M+H] + .

[0288] Step 2: Synthesis of the hydrochloride salt of compound 23 Compound 23-1 (23 mg, 23.64 μmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (539.04 mg, 4.73 mmol) was added at -10 °C and reacted at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatographic column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [water (0.04% HCl)-acetonitrile], acetonitrile %: 20 - 50%, 8 min) to obtain the hydrochloride salt of compound 23. MS m / z = 733.2 [M+H] + . 11H NMR (400 MHz, MeOD) δ ppm 6.93 (d, J = 8.4 Hz, 1 H), 5.68 - 5.51 (m, 1 H), 5.17 - 5.12 (m, 3 H), 4.97 - 4.95 (m, 1 H), 4.75 - 4.72 (m, 1 H), 4.64 (s, 3 H), 4.44 - 4.36 (m, 1 H), 4.05 (s, 2 H), 3.97 - 3.84 (m, 3 H), 3.51 - 3.42 (m, 2 H), 3.31 - 3.27 (m, 3 H), 3.08 (s, 3 H), 2.99 - 2.94 (m, 1 H), 2.71 - 2.58 (m, 2 H), 2.53 - 2.44 (m, 1 H), 2.43 - 2.28 (m, 3 H), 2.27 - 2.07 (m, 2 H), 2.02 (s, 3 H).

[0289] Embodiment 24 [Chemical Structure] Step 1: Synthesis of Intermediate 24-1 Compound 20-2 (0.1 g, 258.22 μmol), water (0.3 mL), 1,4-dioxane (1.5 mL), isopropenylboronic acid pinacol ester (56.41 mg, 335.68 μmol), and potassium carbonate (178.44 mg, 1.29 mmol) were added to a reaction flask. Bis(tri-butylphosphine)palladium (13.20 mg, 25.82 μmol) was added under nitrogen protection, and the mixture was reacted at 80 °C for 12 hours. The reaction solution was cooled to room temperature. 2 mL of water was added to the reaction solution. The reaction solution was extracted with ethyl acetate (2 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin layer chromatography (dichloromethane:methanol = 10:1) was performed to obtain Compound 24-1. MS m / z = 349.0 [M+H] + .

[0290] Step 2: Synthesis of Intermediate 24-2 Under argon protection, methanol (2 mL), wet palladium hydroxide on carbon (20 mg, 14.24 μmol, purity 10%), and compound 24-1 (39 mg, 111.93 μmol) were added into a reaction flask, and the reaction was carried out at 15 Psi and 20 °C for 16 hours while introducing hydrogen. The reaction solution was filtered, and the filter cake was washed with 10 mL of methanol. The filtrate was collected and concentrated under reduced pressure to obtain compound 24-2. MS m / z = 351.2 [M+H] + 。

[0291] Step 3: Synthesis of hydrochloride salt of intermediate 24-3 Compound 24-2 (0.04 g, 114.14 μmol) and hydrochloric acid / methanol (4 M, 0.5 mL) were added to a reaction flask and reacted at 20 °C for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of compound 24-3. MS m / z = 251.2 [M+H] + 。

[0292] Step 4: Synthesis of intermediate 24-4 Compound 4-11B (60 mg, 76.36 μmol) was weighed and dissolved in DMF (1 mL). The hydrochloride salt of compound 24-3 (32.85 mg) was added. Then, DIPEA (1 mL) was added and the reaction was carried out at 50 °C for 1 hour. The reaction solution was cooled to room temperature. 2 mL of water was added to the reaction solution. The reaction solution was extracted with ethyl acetate (3 mL × 4). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol = 10:1) was performed to obtain compound 24-4. MS m / z = 886.3 [M+H] + 。

[0293] Step 5: Synthesis of intermediate 24-5 Compound 24-4 (68 mg, 76.75 μmol) was weighed and dissolved in DCM (1 mL). m-CPBA (10.91 mg, 53.72 μmol, purity 85%) was added, and the reaction was carried out at room temperature (20 °C) for 1 hour. The reaction solution was diluted with 5 mL of dichloromethane, washed twice with 3 mL of 5% sodium thiosulfate solution and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol = 10:1) gave compound 24-5, MS m / z = 902.2 [M+H] + and obtained.

[0294] Step 6: Synthesis of Intermediate 24-6 Compound 5-2 (19.53 mg, 127.49 μmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL). Sodium tert-butoxide (9.80 mg, 101.99 μmol) was added at -15 °C. The reaction system was reacted at -15 °C for 0.25 hour. A 0.5 mL tetrahydrofuran solution of compound 24-5 (23 mg, 25.50 μmol) was added, and the reaction was carried out at 0 °C for 1 hour. 3 mL of saturated aqueous ammonium chloride solution was added to the reaction solution. The reaction solution was extracted with ethyl acetate (2 mL × 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol = 10:1) gave compound 24-6, MS m / z = 991.3 [M+H] + and obtained.

[0295] Step 7: Synthesis of Compound 24 Compound 24-6 (22 mg, 22.20 μmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (253.10 mg, 2.22 mmol) was added at -10 °C, and the reaction was carried out at -10 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Waters Xbridge BEH C18 100×30 mm 5 μm, mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile], acetonitrile %: 30 - 60%, 8 minutes) to obtain Compound 24. MS m / z = 751.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ ppm 6.90 - 6.80 (d, J = 8.4 Hz, 1 H), 5.34 - 5.25 (m, 1 H), 5.21 - 5.13 (m, 1 H), 4.98 - 4.78 (m, 3 H), 4.63 (d, J = 13.6 Hz, 1 H), 4.50 - 4.39 (m, 3 H), 4.10 (s, 2 H), 3.99 (d, J = 14.4 Hz, 1 H), 3.75 - 3.57 (m, 2 H), 3.23 - 3.11 (m, 1 H), 3.00 - 3.17 (m, 6 H), 2.93 (s, 3 H), 2.84 - 2.78 (m, 1 H), 2.66 - 2.77 (m, 2 H), 2.44 - 2.34 (m, 1 H), 2.26 - 2.04 (m, 3 H), 2.02 (s, 3 H), 1.98 - 1.77 (m, 3 H), 1.22 (d, J = 7.2 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H).

[0296] Embodiment 25 [Chemical formula] Step 1: Synthesis of Intermediate 25-1 Compound 20-2 (0.15 g, 387.33 μmol), N,N-dimethylformamide (3 mL), and copper cyanide (104.07 mg, 1.16 mmol) were added to a dried reaction flask. 1,1-Bis(diphenylphosphino)ferrocene palladium chloride (28.34 mg, 38.73 μmol) and tris(dibenzylideneacetone)dipalladium (35.47 mg, 38.73 μmol) were added under nitrogen protection, and the mixture was heated to 120 °C and reacted for 12 hours. The reaction solution was cooled to room temperature. 10 mL of water was added to the reaction solution. The reaction solution was extracted with ethyl acetate (5 mL × 4). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol = 10:1) was performed to obtain Compound 25-1, MS m / z = 333.9 [M+H] + and obtained

[0297] Step 2: Synthesis of hydrochloride salt of Intermediate 25-2 Compound 25-1 (80 mg, 239.96 μmol) and hydrochloric acid / ethyl acetate (4 M, 2 mL) were added to a reaction flask and reacted at 20 °C for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of Compound 25-2. MS m / z = 234.2 [M+H] + .

[0298] Step 3: Synthesis of Intermediate 25-3 Compound 4-11B (120 mg, 152.72 μmol) was weighed and dissolved in DMF (2 mL). The hydrochloride salt of Compound 25-2 (82.39 mg) was added. Then, DIPEA (59.21 mg, 458.16 μmol) was added and the mixture was reacted at 50 °C for 1 hour. The reaction solution was cooled to room temperature. 2 mL of water was added to the reaction solution. The reaction solution was extracted with ethyl acetate (3 mL × 4). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol = 10:1) was performed to obtain Compound 25-3. MS m / z = 869.2 [M+H] + .

[0299] Step 4: Synthesis of Intermediate 25-4 Compound 25-3 (90 mg, 103.57 μmol) was weighed and dissolved in DCM (2 mL). m-CPBA (14.72 mg, 72.50 μmol, purity 85%) was added and reacted at room temperature (20 °C) for 1 hour. The reaction solution was diluted with 5 mL of dichloromethane, washed twice with 3 mL of 5% sodium thiosulfate solution and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol = 10:1) was performed to obtain Compound 25-4 with MS m / z = 885.1 [M+H] + as obtained.

[0300] Step 5: Synthesis of Intermediate 25-5 Compound 5-2 (65.79 mg, 429.41 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL). Sodium tert-butoxide (33.01 mg, 343.53 μmol) was added at -15 °C. The reaction system was reacted at -15 °C for 0.25 hour. 1 mL of a tetrahydrofuran solution of Compound 25-4 (76 mg, 85.88 μmol) was added and the reaction was continued for 1 hour. 5 mL of saturated aqueous ammonium chloride solution was added to the reaction solution. The reaction solution was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 25-5 with MS m / z = 974.2 [M+H] + as obtained.

[0301] Step 6: Synthesis of Compound 25 Compound 25-5 (96 mg, 98.56 μmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (2.25 g, 19.71 mmol, 1.46 mL) was added at -10 °C, and the reaction was carried out at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Waters Xbridge BEH C18 100×30 mm 5 μm, mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile], acetonitrile %: 25 - 55%, 8 minutes) to obtain Compound 25. MS m / z = 734.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 6.87 (d, J = 8.38 Hz, 1 H), 5.20 - 5.18 (m, 1 H), 5.07 - 4.77 (m, 4 H), 4.75 - 4.64 (m, 2 H), 4.60 - 4.47 (m, 1 H), 4.41 - 4.31 (m, 1 H), 4.06 (s, 3 H), 4.01 - 3.56 (m, 4 H), 3.36 - 3.22 (m, 4 H), 3.19 - 3.04 (m, 4 H), 2.97 - 2.90 (m, 1 H), 2.78 - 2.69 (m, 1 H), 2.65 - 2.61 (m, 1 H), 2.41 - 2.25 (m, 2 H), 2.21 - 2.13 (m, 2 H), 2.04 (s, 3 H), 1.96 - 1.84 (m, 2 H), 1.79 - 1.65 (m, 2 H).

[0302] Embodiment 26 [Chemical formula] Step 1: Synthesis of Intermediate 26-1 Compound 21-1 (50 mg, 48.36 μmol) and tributyl(trimethylsilylethynyl)tin (112.37 mg, 290.16 μmol) were dissolved in anhydrous toluene (2 mL). Tetrakis(triphenylphosphine)palladium (11.18 mg, 9.67 μmol) was added, and the reaction was carried out at 130 °C for 16 hours under nitrogen protection. The reaction solution was concentrated. 5 mL of water was added to the reaction solution. The reaction solution was extracted with ethyl acetate (3 mL × 2), washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain Compound 26-1. MS m / z = 1051.3 [M+H] + 。

[0303] Step 2: Synthesis of trifluoroacetate of Intermediate 26-2 Compound 26-1 (50 mg, 47.56 μmol) was dissolved in anhydrous dichloromethane (2 mL). Trifluoroacetic acid (612.82 mg, 5.37 mmol) was added, and the reaction was carried out at 15 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of Compound 26-2. MS m / z = 811.2 [M+H] + 。

[0304] Step 3: Synthesis of Compound 26 The trifluoroacetate of Compound 26-2 (0.1 g) was dissolved in anhydrous methanol (2.5 mL). Potassium carbonate (34.09 mg, 246.63 μmol) was added, and the reaction was carried out at 18 °C for 2 hours. The reaction solution was concentrated. Water (10 mL) and ethyl acetate (5 mL × 2) were added to separate the solution. The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC (chromatography column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [water (0.04% HCl)-acetonitrile], acetonitrile %: 20~50%, 8 minutes). The separated solution was adjusted to pH = 9 with saturated sodium bicarbonate solution, concentrated under reduced pressure to remove the organic phase, extracted with ethyl acetate (5 mL × 2), concentrated under reduced pressure, and lyophilized to obtain Compound 26. MS m / z = 739.2[M+H] + 。

[0305] Embodiment 27

Chemical Formula

[0306] Step 2: Synthesis of the hydrochloride salt of Intermediate 27-2 Compound 27-1 (90 mg, 239.12 μmol) and hydrochloric acid / ethyl acetate (4 M, 2.5 mL) were added to a reaction flask and reacted at 18 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of Compound 27-2. MS m / z = 277.1 [M+H] + .

[0307] Step 3: Synthesis of Intermediate 27-3 Compound 4-11B (100 mg, 127.27 μmol) was weighed and dissolved in DMF (1 mL). The hydrochloride salt of compound 27-2 (42.19 mg) was added. Then, DIPEA (49.34 mg, 381.80 μmol) was added and the reaction was carried out at 50 °C for 1 hour. The reaction solution was cooled to room temperature. Water (10 mL) was added. The reaction solution was extracted with ethyl acetate (5 mL × 3) and separated. The organic phases were combined, extracted with saturated brine (5 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 27-3. MS m / z = 912.1 [M+H] + .

[0308] Step 4: Synthesis of intermediate 27-4 Compound 27-3 (0.14 g, 153.52 μmol) was weighed and dissolved in DCM (2.5 mL). m-CPBA (46.57 mg, 230.28 μmol, purity 85%) was added and the reaction was carried out at 18 °C for 1 hour. The reaction solution was quenched with 20 mL of 5% sodium sulfite solution and extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated to obtain compound 27-4 with MS m / z = 944.1 [M+H] + obtained.

[0309] Step 5: Synthesis of intermediate 27-5 Compound 5-2 (113.63 mg, 741.58 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL). Sodium tert-butoxide (57.01 mg, 593.27 μmol) was added at -15 °C. The reaction system was reacted at -15 °C for 0.25 hour. A 2 mL tetrahydrofuran solution of compound 27-4 (0.14 g, 148.32 μmol) was added and the reaction was continued for 1 hour. 5 mL of saturated ammonium chloride aqueous solution was added to the reaction solution. The reaction solution was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 27-5 with MS m / z = 1017.6 [M+H] + obtained.

[0310] Step 6: Synthesis of the hydrochloride salt of Compound 27 Compound 27-5 (0.12 g, 117.99 μmol) was dissolved in dichloromethane (2.5 mL). Trifluoroacetic acid (766.83 mg, 6.73 mmol) was added at 18 °C, and the reaction was carried out at 18 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [water (0.04% HCl) - acetonitrile], acetonitrile %: 20 - 50%, 8 minutes) to obtain the hydrochloride salt of Compound 27. MS m / z = 777.2 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ = 7.00 - 6.90 (m, 1H), 5.31 - 5.06 (m, 4H), 5.02 - 4.80 (m, 2H), 4.79 - 4.61 (m, 2H), 4.59 - 4.30 (m, 4H), 4.10 - 3.70 (m, 4H), 3.52 - 3.40 (m, 2H), 3.24 - 3.08 (m, 2H), 3.02 - 2.93 (m, 6H), 2.49 - 2.40 (m, 1H), 2.38 - 2.27 (m, 3H), 2.13 - 1.84 (m, 6H).

[0311] Embodiment 28

Chemical formula

[0312] Step 2: Synthesis of Intermediate 28-3 Compound 28-2 (0.154 g, 179.50 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (36.44 mg, 179.50 μmol, purity 85%) was added and the reaction was carried out at room temperature (25 °C) for 1 hour. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated to obtain Compound 28-3 with MS m / z = 874.3 [M+H] + obtained.

[0313] Step 3: Synthesis of Intermediate 28-4 Compound 5-2 (56.50 mg, 368.76 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium tert-butoxide (35.44 mg, 368.76 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 hour. Compound 28-3 (161.14 mg, 184.38 μmol) was added and the reaction was continued for 1 hour. 5 mL of an aqueous solution was added to the reaction solution. The reaction solution was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 28-4 with MS m / z = 963.4 [M+H] + obtained.

[0314] Step 4: Synthesis of the hydrochloride salt of Compound 28 Compound 28-4 (0.173 g, 179.63 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (2.50 g, 21.93 mmol) was added at 20 °C, and the mixture was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile %: 20 - 50%, 10 minutes) to obtain the hydrochloride salt of Compound 28. MS m / z = 723.2 [M+H] + . 1 H NMR (400 MHz, MeOH) δ = 6.99 - 6.90 (m, 1H), 5.38 - 5.29 (m, 2H), 5.26 - 5.11 (m, 2H), 5.10 - 4.95 (m, 2H), 4.75 - 4.66 (m, 2H), 4.55 - 4.47 (m, 1H), 4.38 - 4.28 (m, 2H), 4.20 - 4.07 (m, 1H), 4.00 - 3.90 (m, 2H), 3.85 - 3.69 (m, 2H), 3.42 - 3.35 (m, 1H), 3.28 - 3.20 (m, 2H), 3.20 - 3.07 (m, 6H), 3.05 - 2.95 (m, 2H), 2.91 - 2.79 (m, 1H), 2.43 - 2.16 (m, 8H), 2.08 - 2.01 (m, 3H).

[0315] Embodiment 29 [Chemical formula] Step 1: Synthesis of Intermediate 29-1 Compound 20-6 (0.15 g, 145.92 μmol) and tri-butyl(1-propynyl)tin (384.20 mg, 1.17 mmol) were dissolved in anhydrous toluene (6 mL). Dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (31.00 mg, 43.78 μmol) was added under nitrogen protection, nitrogen was injected and replaced 5 times, and the reaction was carried out at 120 °C for 24 hours. The reaction solution was quenched with 5 mL of water and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (10 mL × 2), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain Compound 29-1. MS m / z = 987.7 [M+H] + 。

[0316] Step 2: Synthesis of Compound 29 Compound 29-1 (67.2 mg, 68.08 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (212.92 mg, 1.87 mmol) was added at 20 °C and reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Welch Xtimate C18 150×25mm×5μm, mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile], acetonitrile %: 40-70%, 9 minutes) to obtain Compound 29. MS m / z = 747.3 [M+H] + 。

[0317] Embodiment 30

Chemical formula

[0318] Step 2: Synthesis of Compound 30-3 Compound 30-2 (264.97 mg, 800.60 μmol) was weighed and dissolved in DMF (3 mL). NCS (160.36 mg, 1.20 mmol) was added to the reaction system and reacted at 55 °C for 2 hours. The reaction mixture was quenched with 5 mL of water, extracted with ethyl acetate (10 mL × 3), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 30-3. MS m / z = 349.2 [M+H] + 。

[0319] Step 3: Synthesis of the hydrochloride salt of Compound 30-4 Compound 30-3 (0.27 g, 735.26 μmol) was weighed. Hydrogen chloride / ethyl acetate (15 mL) was added and reacted at 18 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of Compound 30-4. MS m / z = 249.2 [M+H] + 。

[0320] Step 4: Synthesis of Compound 30-5 Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (5 mL). The hydrochloride salt of compound 30-4 (145.19 mg) was added. Then, DIPEA (98.69 mg, 763.60 μmol) was added and the mixture was reacted at 100 °C for 1 hour. The reaction solution was cooled to room temperature. Water (10 mL) was added. The reaction solution was extracted with ethyl acetate (5 mL × 3) and separated. The organic phases were combined, extracted with saturated brine (5 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 30-5. MS m / z = 884.3 [M+H] + 。

[0321] Step 5: Synthesis of Intermediate 30-6 Compound 30-5 (0.214 g, 241.97 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (49.13 mg, 241.97 μmol, purity 85%) was added and the mixture was reacted at room temperature (18 °C) for 1 hour. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain compound 30-6 with MS m / z = 900.3 [M+H] + and obtained as such.

[0322] Step 6: Synthesis of Intermediate 30-7 Compound 5-2 (71.47 mg, 466.45 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (44.83 mg, 466.45 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 hour. A 5 mL tetrahydrofuran solution of compound 30-6 (0.21 g, 233.23 μmol) was added and the reaction was continued for 1 hour. The reaction solution was quenched with 5 mL of water and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 30-7 with MS m / z = 989.4 [M+H] + and obtained as such.

[0323] Step 7: Synthesis of hydrochloride salt of Compound 30 Compound 30-7 (0.22 g, 222.33 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5.65 g, 49.53 mmol) was added at 20 °C, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl) - acetonitrile], acetonitrile %: 17~47%, 14 minutes) to obtain the hydrochloride salt of Compound 30. MS m / z = 749.3 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ = 7.01 - 6.91 (m, 1H), 5.39 - 5.29 (m, 2H), 5.26 - 5.19 (m, 1H), 5.16 - 5.00 (m, 4H), 4.76 - 4.69 (m, 1H), 4.59 - 4.44 (m, 2H), 4.41 - 4.21 (m, 2H), 4.17 - 4.06 (m, 1H), 4.01 - 3.85 (m, 2H), 3.84 - 3.73 (m, 1H), 3.30 - 3.20 (m, 2H), 3.09 - 2.95 (m, 2H), 2.86 - 2.72 (m, 1H), 2.56 - 2.10 (m, 6H), 2.08 - 1.97 (m, 3H).

[0324] Embodiment 31

Chemical formula

[0325] Step 2: Synthesis of Compound 31-3 Compound 31-2 (0.27 g, 800.60 μmol) was weighed and dissolved in DMF (3 mL). NCS (160.36 mg, 1.20 mmol) was added to the reaction system and reacted at 55 °C for 2 hours. The reaction solution was quenched with 5 mL of water, extracted with ethyl acetate (10 mL × 3), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 31-3. MS m / z = 355.2 [M+H] + 。

[0326] Step 3: Synthesis of trifluoroacetate of Compound 31-4 Compound 31-3 (0.06 g, 160.64 μmol) was weighed. Trifluoroacetic acid (18.32 mg, 160.64 μmol) was added and reacted at 18 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of Compound 31-4. MS m / z = 255.1 [M+H] + 。

[0327] Step 4: Synthesis of Compound 31-5 Compound 4-11B (0.05 g, 63.63 μmol) was weighed and dissolved in DMF (5 mL). The trifluoroacetate salt of compound 31-4 (28.16 mg) was added. Then, DIPEA (24.67 mg, 190.90 μmol) was added and the reaction was carried out at 100 °C for 1 hour. The reaction solution was cooled to room temperature. Water (10 mL) was added. The reaction solution was extracted with ethyl acetate (5 mL × 3) and separated. The organic phases were combined, extracted with saturated brine (5 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 31-5. MS m / z = 890.3 [M+H] + .

[0328] Step 5: Synthesis of intermediate 31-6 Compound 31-5 (0.278 g, 312.22 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (63.39 mg, 312.23 μmol, purity 85%) was added and the reaction was carried out at room temperature (18 °C) for 1 hour. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain compound 31-6 with MS m / z = 906.3 [M+H] + and obtained.

[0329] Step 6: Synthesis of intermediate 31-7 Compound 5-2 (81.14 mg, 529.58 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Sodium tert-butoxide (50.89 mg, 529.58 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 hour. A 5 mL tetrahydrofuran solution of compound 31-6 (0.24 g, 264.79 μmol) was added and the reaction was continued for 1 hour. The reaction solution was quenched with 5 mL of water and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 31-7 with MS m / z = 995.4 [M+H] + and obtained.

[0330] Step 7: Synthesis of hydrochloride salt of Compound 31 Compound 31-7 (0.05 g, 50.23 μmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (157.08 mg, 1.38 mmol) was added at 20 °C, and the mixture was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Phenomenex C18 80×40 mm×3 μm, mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile], acetonitrile %: 57 - 87%, 8 minutes) to obtain the hydrochloride salt of Compound 31. MS m / z = 755.2 [M+H] + .

[0331] Embodiment 32 [Chemical formula] Step 1: Synthesis of Intermediate 32-2 Methyl 3,5-dicarboxylate pyrazole (6.5 g, 35.30 mmol) and Compound 32-1 (10.56 g, 35.30 mmol) were added to N,N-dimethylformamide (60 mL). Then, potassium carbonate (9.76 g, 70.59 mmol) was added. The reaction solution was heated to 100 °C, stirred, and reacted under nitrogen protection for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. 500 mL of ethyl acetate was added to the crude product, stirred for 5 minutes, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 32-2. HNMR: (400 MHz, CDCl3) δ: 7.34 (m, 1H), 4.69 (t, J = 6.8 Hz, 2H), 4.49 (br s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.83 - 3.64 (m, 1H), 2.12 - 2.05 (m, 1H), 1.99 - 1.83 (m, 1H), 1.44 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H).

[0332] Step 2: Synthesis of Intermediate 32-3 Compound 32-2 (11.5 g, 32.36 mmol) was dissolved in DCM (10 mL). Then, hydrogen chloride / ethyl acetate (4 M, 40.45 mL) was added. The reaction mixture was stirred and reacted at 15 °C for 4 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain a residue. Water (30 mL) and dichloromethane (50 mL) were added to the residue. Then, the pH was adjusted to 9 with 2 M sodium hydroxide solution. The organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 32-3.

[0333] Step 3: Synthesis of Intermediate 32-4 Compound 32-3 (8.3 g, 32.51 mmol) was dissolved in anhydrous methanol (50 mL). Then, sodium methoxide (3.51 g, 65.03 mmol) was added and stirred, and reacted at 60 °C for 15 hours under nitrogen protection. The reaction mixture was cooled to room temperature and filtered. The solid was collected and dried in vacuo for 0.5 hour to obtain Compound 32-4. HNMR: (400 MHz, CDCl3) δ: 7.34 (s, 1H), 6.10 (br s, 1H), 4.65 (ddd, J =3.6, 6.8, 14.3 Hz, 1H), 4.49 (ddd, J =5.9, 10.3, 14.3 Hz, 1H), 3.95 (s, 3H), 3.68 - 3.52 (m, 1H), 2.46 - 2.33 (m, 1H), 2.09 - 1.95 (m, 1H), 1.37 (d, J =6.4 Hz, 3H).

[0334] Step 4: Synthesis of Intermediate 32-5 Compound 32-4 (4.05 g, 18.14 mmol) was dissolved in tetrahydrofuran (80 mL). Lithium aluminum hydride (2.75 g, 72.57 mmol) was slowly added in several portions. Then, the reaction mixture was stirred and reacted at 20 °C for 2 hours, and then slowly heated to 60 °C, stirred, and reacted for 15 hours. The reaction mixture was cooled to 0 °C. Then, 2.8 mL of water and 2.8 mL of 15% sodium hydroxide solution were slowly added to quench the reaction. The reaction mixture was stirred for 10 minutes, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain Compound 32-5. (400 MHz, CDCl3) δ: 6.07 (s, 1H), 4.61 (s, 2H), 4.53 - 4.40 (m, 1H), 4.25 - 4.05 (m, 2H), 3.72 (d, J = 15.6 Hz, 1H), 3.10 - 2.96 (m, 1H), 1.98 - 1.90 (m, 1H), 1.57 - 1.45 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H).

[0335] Step 5: Synthesis of Intermediate 32-6 Compound 32-5 (2.80 g, 15.45 mmol) was dissolved in dichloromethane (30 mL). Then, tert-butoxycarbonyl anhydride (3.37 g, 15.45 mmol, 3.55 mL) was added. The reaction mixture was stirred and reacted at 15 °C for 15 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure. Methanol (20 mL) and water (20 mL) were added to the residue. Then, potassium carbonate (4.27 g, 30.90 mmol) was added. The resulting system was heated to 80 °C, stirred, and reacted for 8 hours. The reaction mixture was concentrated under reduced pressure and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 32-6. 1H NMR: (400 MHz, CDCl3) δ: 6.07 (br s, 1H), 5.12 - 4.67 (m, 1H), 4.60 (s, 2H), 4.46 - 4.34 (m, 1H), 4.17 - 3.89 (m, 2H), 2.45 (br s, 1H), 2.26 - 2.12 (m, 1H), 2.04 - 1.79 (m, 1H), 1.50 - 1.30 (m, 9H), 1.24 (d, J = 5.8 Hz, 3H).

[0336] Step 6: Synthesis of Intermediate 32-7 Compound 32-6 (4.3 g, 15.28 mmol) was dissolved in dichloromethane (100 mL). The resulting solution was cooled to 0 °C. Then, Dess-Martin periodinane (6.48 g, 15.28 mmol) was slowly added. Thereafter, the ice bath was removed. The reaction mixture was heated to room temperature (20 °C), stirred, and reacted for 3 hours. The reaction mixture was quenched with 30 mL of saturated sodium bicarbonate solution. The organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 32-7. 11H NMR: (400 MHz, CDCl3) δ: 9.92 - 9.85 (m, 1H), 6.62 (br s, 1H), 5.17 - 4.33 (m, 3H), 4.24 (dd, J = 10.1, 14.1 Hz, 1H), 4.02 (br d, J = 16.6 Hz, 1H), 2.33 - 2.19 (m, 1H), 2.03 - 1.89 (m, 1H), 1.39 (br s, 9H), 1.30 - 1.26 (m, 3H).

[0337] Step 7: Synthesis of Intermediate 32-8 Compound 32-7 (2.0 g, 7.16 mmol) was dissolved in dimethyl sulfoxide (25 mL). Subsequently, a solution of potassium dihydrogen phosphate (2.53 g, 18.62 mmol) in water (5 mL) was added. Then, a solution of sodium chlorite (1.36 g, 15.04 mmol) in water (5 mL) was added dropwise, and the mixture was stirred and reacted at 20 °C for 2 hours. The reaction solution was diluted with 200 mL of ethyl acetate and then washed with water (40 mL × 2) and 40 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 32-8. 1H NMR: (400 MHz, CDCl3) δ: 6.69 (br s, 1H), 5.18 - 4.34 (m, 3H), 4.24 (br dd, J = 10.3, 14.1 Hz, 1H), 4.03 (br d, J = 16.6 Hz, 1H), 2.32 - 2.18 (m, 1H), 2.00 (br s, 1H), 1.40 (br s, 9H), 1.27 (d, J = 6.8 Hz, 3H).

[0338] Step 8: Synthesis of Intermediate 32-9 Compound 32-8 (1.0 g, 3.39 mmol) was dissolved in tetrahydrofuran (15 mL). Subsequently, carbonyldiimidazole (823.56 mg, 5.08 mmol) was added, and the mixture was stirred and reacted at 10 °C for 1 hour under nitrogen protection. Then, a dimethylamine / tetrahydrofuran solution (2 M, 5.08 mL) was added. The resulting reaction solution was stirred, and the reaction was continued for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (50 mL) and washed with water (10 mL × 3). The organic phase was dried, filtered, and concentrated under reduced pressure to obtain crude compound 32-9. 1 H NMR: (400 MHz, CDCl3) δ: 6.46 (s, 1H), 5.18 - 4.30 (m, 3H), 4.22 - 4.10 (m, 1H), 4.00 (d, J = 16.8 Hz, 1H), 3.32 (br s, 3H), 3.08 (s, 3H), 2.29 - 2.16 (m, 1H), 2.03 - 1.88 (m, 1H), 1.50 - 1.31 (m, 9H), 1.26 (d, J = 6.8 Hz, 3H).

[0339] Step 9: Synthesis of Intermediate 32-10 Compound 32-9 (1.03 g, 3.19 mmol) was dissolved in N,N-dimethylformamide (10 mL). Subsequently, N-chlorosuccinimide (853.21 mg, 6.39 mmol) was added. The resulting reaction solution was stirred and reacted at 55 °C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 32-10 with MS m / z = 357.0 [M+H] + and obtained.

[0340] Step 10: Synthesis of the hydrochloride salt of Intermediate 32-11 Compound 32-10 (300 mg, 622.12 μmol) was dissolved in dichloromethane (0.5 mL). Then, hydrogen chloride / ethyl acetate solution (4 M, 1.56 mL) was added. The resulting reaction solution was stirred and reacted under nitrogen protection at 20° C. for 0.5 hours. The reaction solution was concentrated under reduced pressure to give crude compound 32-11 hydrochloride salt. MS m / z= 257.0 [M+H] + .

[0341] Step 11: Synthesis of intermediate 32-12 Compound 4-11B (200 mg, 254.53 μmol) was weighed and dissolved in DMF (1.5 mL). Compound 32-11 hydrochloride (217.00 mg) was added. Then DIPEA (164.48 mg, 1.27 mmol) was added and reacted at 100° C. for 1 hour. The reaction solution was cooled to room temperature. Water (10 mL) was added. The reaction solution was extracted with ethyl acetate (5 mL×3) and separated. The organic phases were mixed, extracted with saturated saline (5 mL×2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain compound 32-12. MS m / z =892.4 [M+H] + .

[0342] Step 12: Synthesis of intermediate 32-13 Compound 32-12 (58 mg, 64.99 μmol) was weighed and dissolved in DCM (1 mL). m-CPBA (13.19 mg, 64.99 μmol, purity 85%) was added and reacted at room temperature (18° C.) for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 32-13, MS m / z =908.3 [M+H]. + I got it at.

[0343] Step 13: Synthesis of intermediate 32-14 Compound 5-2 (39.13 mg, 255.39 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium tert-butoxide (24.54 mg, 255.39 μmol) was added at 0 °C. The reaction system was reacted at 0 °C for 1 hour. Compound 32-13 (58 mg, 63.85 μmol) was added and the reaction was continued for 1 hour. The reaction solution was quenched with 0.5 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 32-14, MS m / z = 997.4 [M+H] + and obtained.

[0344] Step 14: Synthesis of hydrochlorides of Compounds 32A and 32B Compound 32-14 (36 mg, 36.09 μmol) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (chromatography column: Xtimate C18 150×40 mm×5 μm, mobile phase: [water (0.05% HCl)-acetonitrile], acetonitrile%: 30-60%) to obtain hydrochlorides of Compounds 32A and 32B. Liquid phase analysis: chromatography column: ChromCore 120 C18 3 μm, 3.0×30 mm, mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)], acetonitrile (0.02% trifluoroacetic acid)%: 10% - 80%, 7 minutes_220&254 nm, retention time: 32A (Rt = 3.484 minutes), MS m / z = 757.1 [M+H] + , 32B (Rt = 3.606 minutes), MS m / z = 757.2 [M+H] + .

[0345] Biological test data: Experimental Example 1. Antiproliferative effect of the compound on tumor cell line AsPC-1 Research objective This experiment was on KRAS G12DBy detecting the effect of a compound on the in vitro cell activity of the mutant tumor cell line AsPC-1, the anti-proliferative effect of the compound is studied.

[0346] Experimental materials The cell line was AsPC-1. The type of tumor was pancreatic cancer. The cell line was cultured by adherent growth using RPMI 1640 + 10% FBS.

[0347] Ultra Low Cluster-96 well plate (Corning-7007)

[0348] Greiner CELLSTAR 96 well plate (#655090)

[0349] Promega CellTiter-Glo 3D luminescent cell viability assay kit (Promega-G9683)

[0350] 2104-10 EnVision reader (PerkinElmer)

[0351] RPMI 1640, DMEM, PBS (phosphate buffer solution), FBS (fetal bovine serum), antibiotics-antifungals, L-glutamine, and DMSO (dimethyl sulfoxide)

[0352] Experimental methods and steps Cell culture Under the culture conditions shown in the culture method, the tumor cell line was incubated in an incubator at 37°C and 5% CO2. Subculture was performed routinely, and cells in the logarithmic growth phase were collected and seeded.

[0353] Cell seeding Cells were stained with trypan blue and the number of viable cells was counted.

[0354] The cell concentration was adjusted to an appropriate concentration.

[0355] The cell line was AsPC-1 and the density was 7,000 cells (per well).

[0356] The cell suspension is added to the ULA culture plate at a density of 135 μL per well, and the same volume of cell-free medium is added to the blank control plate.

[0357] Immediately after seeding, the ULA culture plate was centrifuged at room temperature at 1,000 rpm for 10 minutes. Note: To avoid unnecessary shaking, all subsequent operations after centrifugation should be carried out with care.

[0358] The culture plates were incubated overnight in an incubator at 37 °C, 5% CO2, and 100% relative humidity.

[0359] Preparation of 10X compound standard solution and cell treatment with the compound (Day 1) After preparing the 10X compound standard solution (DMSO 10X standard solution), 15 μL of the 10X compound standard solution was added to the ULA culture plate, and 15 μL of the DMSO-cell medium mixture was added to the vehicle control and the blank control.

[0360] The 96-well cell plate was returned to the incubator and incubated for 120 hours.

[0361] The spheroid formation of the cells was observed daily until the end of the experiment.

[0362] CellTiter-Glo Luminescent Cell Viability Assay (Day 5) The following steps were performed according to the instructions of the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0363] Add the CellTiter-Glo 3D reagent at a density of 150 μL per well (equal to the volume of cell medium per well). To avoid light, the cell plate was wrapped with aluminum foil.

[0364] The culture plate was shaken on an orbital shaker for 5 minutes.

[0365] The mixture was carefully aspirated and dispensed 10 times with a pipette to mix the mixture in the well. Before proceeding to the next step, it is necessary to ensure that the cell spheroids are sufficiently separated.

[0366] Next, the solution in the ULA plate was transferred into a black plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescence signal.

[0367] The luminescence signal was detected with a 2104 EnVision reader.

[0368] Data analysis The inhibition rate (IR) of the detected compound was calculated using the following formula: IR (%) = (1 - (RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control)) × 100%. The inhibition rates of the compounds at various concentrations were calculated in Excel, and then an inhibition curve diagram was created, and the minimum inhibition rate, maximum inhibition rate, and IC 50 and related parameters including were calculated using GraphPad Prism software.

[0369] Experimental results The results are shown in Table 1.

Table 3

[0370] The conclusion of the experiment is that the compound of the present invention has an excellent anti-proliferative effect against KRAS G12D mutant AsPC-1 cells.

[0371] Experimental Example 2. AsPC-1 cell proliferation assay 1. Purpose KRAS G12D Compounds that can effectively inhibit the proliferation of mutant AsPC-1 cells were screened by the 3D-CTG method.

[0372] 2. Experimental materials: ASPC-1 cells from ATCC, RPMI-1640 medium from ATCC, fetal bovine serum from Ausgenex, CellTiter-Glo® 3D assay kit (3D-CTG) from Promega, and CellCarrier-96 Spheroid ULA / CS from PE.

[0373] 3. Experimental method: 1) ASPC-1 cells were seeded in a transparent 96-well cell culture plate at a density of 195 μL of cell suspension per well (containing 2,000 cells).

[0374] 2) The test compound was diluted to 10 mM with 100% DMSO as the first concentration, and then serially diluted 5-fold with a pipette up to the eighth concentration (i.e., from 10 mM to 0.13 μM). 2 μL of the serially diluted compound was added to 48 μL of cell culture medium for secondary dilution. After mixing, 5 μL of the secondarily diluted compound was added to the corresponding well of the cell plate containing 195 μL of cells. The cell plate was placed in a carbon dioxide incubator and incubated for 7 days. At this point, the concentration of the compound was 10 μM - 0.128 nM, and the DMSO concentration was 0.1%.

[0375] 3) After incubation, 100 μL of the cell supernatant was discarded, and 3D-CTG was added at a density of 60 μL per well. The cells were shaken and incubated at room temperature and 200 rpm for 20 minutes, and then incubated at room temperature in the incubator for 1 hour.

[0376] 4) 100 μL of the supernatant was pipetted from the well plate to a 96-well black plate with a clear bottom, and luminescence was read with a BMG.

[0377] 4. Data analysis: The original data was converted to inhibition rate using the formula Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L), and IC was determined by four-parameter curve fitting (log(inhibitor) vs. response - Variable slope mode in GraphPad Prism).50 The value was obtained.

[0378] H well: Reading value of DMSO well L well: Reading value of medium

[0379] 5. Experimental results The results are shown in Table 2. [Table 4]

[0380] The conclusion of the experiment is that the compound of the present invention has an excellent anti-proliferation effect on KRAS G12D mutant AsPC-1 cells.

[0381] Experimental Example 3. H727 cell proliferation assay 1. Purpose KRAS G12V Compounds capable of effectively inhibiting the proliferation of mutant H727 cells were screened by the 3D-CTG method.

[0382] 2. Experimental materials: H727 cells from ATCC, RPMI-1640 medium from ATCC, fetal bovine serum from Ausgenex, CellTiter-Glo® 3D assay kit (3D-CTG) from Promega, and CellCarrier-96 Spheroid ULA / CS from PE.

[0383] 3. Experimental method: 5) The above-mentioned cells were seeded in a transparent 96-well cell culture plate at a density of 195 μL of cell suspension per well (containing 2,000 cells).

[0384] 6) The test compound was diluted to 10 mM with 100% DMSO as the first concentration, and then serially diluted 5-fold by pipetting up to the eighth concentration (i.e., from 10 mM to 0.13 μM). 2 μL of the serially diluted compound was added to 48 μL of cell culture medium for secondary dilution. After mixing, 5 μL of the secondarily diluted compound was added to the corresponding wells of a cell plate containing 195 μL of cells. The cell plate was placed in a carbon dioxide incubator and incubated for 7 days. At this point, the concentration of the compound was 10 μM to 0.128 nM, and the DMSO concentration was 0.1%.

[0385] 7) After incubation, 100 μL of the cell supernatant was discarded, and 3D-CTG was added at a density of 60 μL per well. The cells were shaken and incubated at room temperature and 200 rpm for 20 minutes, and then incubated at room temperature in the incubator for 1 hour.

[0386] 8) 100 μL of the supernatant was pipetted from the well plate to a 96-well black plate with a clear bottom, and luminescence was read using a BMG.

[0387] 4. Data analysis: The original data was converted to inhibition rate using the formula Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L), and the IC50 value was obtained by four-parameter curve fitting (log(inhibitor) vs. response - Variable slope mode in GraphPad Prism).

[0388] Well H: Reading value of the DMSO well Well L: Reading value of the medium

[0389] 5. Experimental results The results are shown in Table 3.

Table 5

[0390] The conclusion of the experiment is that the compound of the present invention is KRAS G12VIt is said to have an excellent anti-proliferation effect against mutant H727 cells.

[0391] Experimental Example 4. SW620 Cell In Vitro Proliferation Assay Experimental Materials: RPMI1640 medium, penicillin / streptomycin antibiotics by Gibco, and fetal bovine serum by Hyclone. 3D CellTiter-Glo (Cell Viability Chemiluminescence Assay) reagent by Promega. SW620 (KRAS G12V mutation) cell line by ATCC, Envision Multilabel Analyzer (PerkinElmer).

[0392] Experimental Method: Cells were seeded in a 96-well ultra-low adsorption U-plate at a density of 80 μL of cell suspension per well (containing 1,000 cells). The cell plate was incubated overnight in a carbon dioxide incubator.

[0393] Using a multi-channel pipette, the test compound was serially diluted 8-fold (i.e., from 2 mM to 25.6 nM) and replicated in duplicate. 78 μL of medium was added to an intermediate plate. Then, according to the corresponding positions, the serially diluted compound was transferred to the intermediate plate at a density of 2 μL per well, mixed, and transferred to the cell plate at a density of 20 μL per well. The concentration range of the compound transferred into the cell plate was 10 μΜ - 0.128 nM. The cell plate was incubated in a carbon dioxide incubator for 10 days. Another cell plate was prepared and the signal value read on the addition day was treated as the maximum value (Max value in the following formula) and used for data analysis.

[0394] The cell viability chemiluminescence assay reagent was added to the cell plate at a density of 100 μL per well and incubated at room temperature for 30 minutes to stabilize the luminescence signal. Reading was performed using a multi-label analyzer.

[0395] Data Analysis: The original data was converted to the inhibition rate using the formula (Sample - Min) / (Max - Min)×100%, and the IC 50 value was obtained by four - parameter curve fitting (the "log(inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 4 shows the inhibitory activity of the compounds of the present invention against the proliferation of SW620 cells.

Table 6

[0396] The conclusion of the experiment is that the compounds of the present invention have an excellent anti - proliferation effect against KRAS G12V mutant SW620 cells.

[0397] Experimental Example 5. LU99 cell in vitro proliferation assay Experimental materials: RPMI1640 medium, penicillin / streptomycin antibiotics by Gibco, and fetal bovine serum by Hyclone. 3D CellTiter - Glo (cell viability chemiluminescence assay) reagent by Promega. LU99 (KRAS G12C mutant) cells by JCRB, Envision Multilabel analyzer (PerkinElmer).

[0398] Experimental method: Cells were seeded in a 96 - well ultra - low - attachment U - plate at a density of 80 μL of cell suspension per well (containing 1,000 cells). The cell plate was incubated overnight in a carbon dioxide incubator.

[0399] Using a multi-channel pipette, a 5-fold dilution of the test compound was performed up to the 8th concentration (i.e., from 2 mM to 25.6 nM) and replicated in duplicate. 78 μL of the medium was added to the intermediate plate. Then, according to the corresponding positions, the serially diluted compound was transferred to the intermediate plate at a density of 2 μL per well, mixed, and then transferred to the cell plate at a density of 20 μL per well. The concentration range of the compound transferred into the cell plate was 10 μΜ - 0.128 nM. The cell plate was incubated in a carbon dioxide incubator for 10 days. Another cell plate was prepared and used for data analysis with the signal value read on the addition day as the maximum value (Max value in the following formula).

[0400] The cell viability chemiluminescence assay reagent was added to the cell plate at a density of 100 μL per well and incubated at room temperature for 30 minutes to stabilize the luminescence signal. The reading was performed using a multi-label analyzer.

[0401] Data analysis: The original data was converted to the inhibition rate using the formula (Sample - Min) / (Max - Min)×100%, and the IC 50 value was obtained by four-parameter curve fitting (the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism). Table 5 shows the inhibitory activity of the compound of the present invention against the proliferation of LU99 cells.

Table 7

[0402] The conclusion of the experiment is that the compound of the present invention has an excellent anti-proliferative effect against KRAS G12C mutant LU99 cells.

[0403] Experimental Example 6. MKN-1 cell in vitro proliferation assay Experimental materials: RPMI 1640 medium, penicillin / streptomycin antibiotics by Gibco, and fetal bovine serum by Hyclone. 3D CellTiter-Glo (Cell viability chemiluminescence assay) reagent by Promega. MKN-1 (KRAS WT amplified) cells by JCRB, Envision Multilabel Analyzer (PerkinElmer).

[0404] Experimental method: Cells were seeded in 96-well ultra-low attachment U-plates at a density of 80 μL of cell suspension per well (containing 1,000 cells). The cell plates were incubated overnight in a carbon dioxide incubator.

[0405] Using a multi-channel pipette, a 5-fold dilution of the test compound was performed up to the 8th concentration (i.e., from 2 mM to 25.6 nM), and it was replicated in duplicate. 78 μL of medium was added to the intermediate plate. Then, according to the corresponding positions, the serially diluted compound was transferred to the intermediate plate at a density of 2 μL per well, mixed, and transferred to the cell plate at a density of 20 μL per well. The concentration range of the compound transferred into the cell plate was 10 μΜ - 0.128 nM. The cell plates were incubated in a carbon dioxide incubator for 10 days. Another cell plate was prepared and used for data analysis with the signal value read on the addition day as the maximum value (Max value in the following formula).

[0406] The cell viability chemiluminescence assay reagent was added to the cell plates at a density of 100 μL per well and incubated at room temperature for 30 minutes to stabilize the luminescence signal. Reading was performed using a multi-label analyzer.

[0407] Data analysis: The original data was converted to the inhibition rate using the formula (Sample - Min) / (Max - Min)×100%, and the IC was determined by 4-parameter curve fitting (in the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism). 50Values were obtained. Table 6 shows the inhibitory activity of the compounds of the present invention against the proliferation of MKN-1 cells.

Table 8

[0408] The conclusion of the experiment is that the compounds of the present invention have excellent anti-proliferation effects against KRAS WT amplified MKN-1 cells.

[0409] Experimental Example 7. Study on the drug efficacy in vivo Experimental method: Establishment of a Balb / c nude mouse model with subcutaneous xenograft of human colorectal cancer GP2D cells: On the right back of each mouse, 0.2 mL (2×10 6 ) of GP2D cells (Matrigel was added at a volume ratio of 1:1) was subcutaneously inoculated. The mice were divided into groups (6 or 4 mice in each group), and administration was carried out when the average tumor volume reached 270 mm 3 . On the experimental day, the corresponding drugs were administered to the mice according to the groups. The first group G1 was set as the vehicle group, and 5% DMSO + 95% (10% HP-β-CD) was administered intragastrically alone. The second group G2 was administered the hydrochloride salt of compound 14 (vehicle: 5% DMSO + 95% (10% HP-β-CD)). The dosage and administration schedule are shown in Table 7.

Table 9

[0410] During the experiment, the body weight and tumor size of the animals were measured twice a week, and the clinical symptoms of the animals were observed and recorded daily. The most recently measured body weight of the animals was adopted as the reference for each dosage.

[0411] The length (a) and width (b) of the tumor were measured using a digital caliper. The calculation formula for the tumor volume (TV) is TV = a×b 2 / 2.

[0412] Experimental results: The hydrochloride salt of Compound 14 has a significant inhibitory effect on human colorectal cancer GP2D mouse xenografts. 28 days after administration, the tumor volume inhibition rate TGI (%) of Group G2 (150 mg / kg, PO, BID) was 97.2 on the 28th day. The detailed results are shown in Table 8.

Table 10

[0413] The conclusion of the experiment is that the compound of the present invention has an excellent tumor inhibitory effect in the GP2D cell line from the perspective of in vivo drug efficacy.

[0414] Experimental Example 8. Research on in vivo drug efficacy Experimental method: Establishment of a Balb / c nude mouse model with subcutaneous xenotransplantation of human pancreatic cancer Panc0403 cells: 0.2 mL (5×10 6 ) of Panc0403 cells were subcutaneously inoculated on the right back of each mouse. The mice were divided into groups (6 or 4 mice in each group), and administration was carried out when the average tumor volume reached 190 mm 3 . On the experimental day, the corresponding drug was administered to the mice according to the group. The first group G1 was set as the vehicle group, and 5% DMSO + 95% (10% HP-β-CD) was administered intragastrically alone. The second group G2 was administered Compound 4A (vehicle: 5% DMSO + 95% (10% HP-β-CD)). The dosage and administration schedule are shown in Table 9.

Table 11

[0415] During the experiment, the body weight and tumor size of the animals were measured twice a week, and the clinical symptoms of the animals were observed and recorded daily. The most recently measured body weight of the animals was adopted as the standard for each dosage.

[0416] The length (a) and width (b) of the tumor were measured using a digital caliper. The calculation formula for tumor volume (TV) is TV = a×b 2 / 2.

[0417] Experimental results: Compound 4A has a significant inhibitory effect on human pancreatic cancer Panc0403 mouse xenografts. 28 days after administration, the tumor volume inhibition rate TGI (%) of Group G2 (150 mg / kg, PO, BID) was 113.7 on the 28th day. Table 10 shows the detailed results. [Table 12]

[0418] The conclusion of the experiment is that the compound of the present invention has an excellent tumor inhibitory effect in the Panc0403 cell line from the perspective of the drug efficacy in vivo.

Claims

[Claim 1] The inventions described herein.

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