Pyrrolyl amide compounds, methods of making and uses thereof

Abstract

The application discloses a pyrrole amide compound, a preparation method and application thereof. The structure of the compound is shown in formula (I). The compound is a new anti-HBV compound. The application further discloses a pharmaceutical composition containing the compound as an active ingredient, which can be used for treating and / or preventing HBV infection, and has important application value.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a pyrrolamide compound for treating HBV infection, its preparation method, and its uses. Background Technology

[0002] Hepatitis B virus (HBV), which causes hepatitis B, remains one of the most concerning viruses globally. Currently, over 250 million people worldwide carry HBV, and these individuals have an increased risk of developing serious liver diseases, including cirrhosis, permanent liver scarring, liver failure, and cancer. The World Health Organization estimates that more than 780,000 people die from hepatitis B each year. According to data from the Hepatitis B Foundation, HBV accounts for 80% of factors inducing liver cancer, and the five-year survival rate for liver cancer patients is typically only 15%.

[0003] Despite the existence of effective vaccines, vaccination coverage remains unsatisfactory in areas where HBV is prevalent. [1] Currently, two main classes of drugs are approved for the treatment of chronic hepatitis B. One class is interferon (IFN-α) and its pegylated form (Peg-IFN-α). IFN-α is an immunomodulator that can nonspecifically induce the expression of interferon-stimulated genes (ISGs). These genes encode constitutive or secretory proteins with direct or indirect antiviral properties, thereby promoting the differentiation or activation of immune cells. [2] After 48 weeks of subcutaneous IFN-α injections, the response rate in HBV patients was only 25%. [3]Besides its low response rate, IFN-α also has other drawbacks, such as the need for injection, adverse reactions like severe flu-like symptoms, and contraindications in patients with compensated cirrhosis, severe hepatitis, and concurrent autoimmune or psychological disorders. Another class of approved drugs are nucleoside analogs (NAs), of which five are currently approved: lamivudine (LMV), telbivudine (Ldt), adefovir dipivoxil (ADV), tenofovir (TFV), and entecavir (ETV). NAs reduce viral particles by directly inhibiting HBV polymerase activity, thereby interrupting the nucleocapsid-to-nucleus cycle of infected cells and theoretically reducing cccDNA expression. However, NAs treatment failed to inhibit de novo synthesis of cccDNA in newly infected cells, indicating that residual viral particles during antiviral treatment can lead to infection of new cells and reconstruction of the cccDNA library. If patients discontinue medication on their own, virological rebound may occur. Therefore, functional cure of chronic hepatitis B virus infection is rare, and most patients require lifelong medication. However, long-term use of NAs can easily lead to viral mutation and drug resistance.

[0004] Given the limitations of current therapies, several drugs targeting the HBV replication cycle or enhancing the human immune response are under development and have entered clinical trials. Among these, core proteins in the HBV replication process are crucial for the packaging and reverse transcription of HBV pgRNA. Molecules targeting these proteins are called core protein allosteric regulators or capsid assembly regulators (CpAMs). Based on their mechanisms of action, CpAMs can be divided into two categories: Class I CpAMs, represented by heteroaryl dihydropyrimidines (HAPs), enhance nucleocapsid formation kinetics, leading to misassembly of the nucleocapsid; and Class II CpAMs, represented by phenylacrylamide (PPAs) and sulfadiazine (SBAs) structures, accelerate nucleocapsid assembly, forming morphologically normal nucleocapsids that lack viral pgRNA and HBV polymerase encapsulation. [4] .

[0005] Antiviral studies of nucleocapsid inhibitors BAY41-4109 (HAP) and JNJ-632 (SBA) with different mechanisms in human primary hepatocytes revealed that CpAMs not only inhibit HBV replication but also suppress HBV RNA transcription and antigen production, suggesting that CpAMs possess a dual mechanism of action in inhibiting both early and late stages of viral infection. [5-6] NVR3-778 (SBA), as an early-developed CpAM molecule, exhibited strong anti-HBV activity, showing positive results in ECG activity in HepG2.2.15 cells.50 The concentration was 0.4 μM. Similarly, it also showed effective anti-HBV activity in a humanized liver mouse model infected with HBV. [7] With the advancement of science and technology, drug developers have designed and screened molecular structures with in vitro anti-HBV activity at the nM level, such as GLP-26 and RG7907.

[0006] Currently, most anti-HBV drugs exhibit good in vitro anti-HBV activity. However, after entering clinical trials, some drugs have failed due to low efficacy and adverse reactions such as elevated ALT and relapse after drug withdrawal. Therefore, despite the availability of numerous drugs and methods for treating HBV, novel molecular structures and mechanisms of action for achieving a cure for hepatitis B remain urgently needed in the field of HBV treatment. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a compound with excellent anti-HBV activity and a novel structure.

[0008] To address the aforementioned technical problems, the present invention provides a compound of formula (I), or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0009]

[0010] Among them, R1 is selected from -H, C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Deuterated alkoxy groups, halogens, and cyano groups;

[0011] R2 is selected from -H, C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 1-8 Deuterated alkyl, C 1-8 Hydroxyalkyl, C2-8 ynyl;

[0012] R3 is selected from substituted or unsubstituted C3. 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; said 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; said C 6-10 The substituents of the aryl group are selected from halogens, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 The substituents of the 5-10 membered heteroaryl group are selected from halogens and C. 1-8Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, -CN;

[0013] R4 is selected from substituted or unsubstituted C4. 1-10 Alkyl, substituted or unsubstituted C 3-14 Cycloalkyl, substituted or unsubstituted 4-14 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-10 Aryl, C 2-8 acetylinyl

[0014] The C 1-10 The alkyl substituents are selected from -H, deuterium, halogen, -OH, -COOH, and -C(O)NR. a R b substituted or unsubstituted 5-6 aryl groups, C 3-8 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclic alkyl, C 1-8 Alkoxy, C 2-8 The 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the 5-6-membered heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O, and S; the -CH2- on the 5-6-membered heterocyclic alkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituents of the 5-6-membered heteroaryl group are selected from halogens, C... 1-8 Alkyl, -NH2, -OH, -CF3; the substituents of the 5-6 membered heterocyclic alkyl group are selected from -OH, C 1-8 Alkyl; R a R b Each is independently selected from -H, C 1-4 alkyl;

[0015] The C 3-14 The -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-14 The substituents of the cycloalkyl group are selected from -H, deuterium, and C. 1-8 Hydroxyalkyl, -C(O)NH2, -OH, -COOH, halogen, substituted or unsubstituted 5-6 membered heteroaryl, -CF3, C 1-8 Alkyl, -NH2, C 1-8 Alkoxy, -NHC(O)CH3, -NHS(O)2CH3, C 2-8 The 5-6 membered heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-8 Haloalkyl, C 1-8 alkyl;

[0016] The -CH2- on the 4-14 membered heterocyclic alkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-14 membered heterocyclic alkyl ring contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-14 membered heterocyclic alkyl ring are selected from C. 1-8 Hydroxyalkyl, -CF3, -OH, -COOH, C 1-8 Alkyl, C 1-8 Carbonyl, -S(O)2CH3, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 2-8 The alkynyl group or halogen-substituted phenyl group; the 4-6 membered heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S;

[0017] The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 5-10 membered heteroaryl group are selected from C. 1-8 Alkyl, halogen, -COOH, -CF3;

[0018] The C 6-10 The substituents of the aryl group are selected from halogens, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -COOH, -B(OH)2;

[0019] R5 is selected from -H, deuterium, and -OH; R6 is selected from -H, deuterium, and C. 1-8 Alkyl group, -NH2; m is selected from 0 or 1;

[0020] Ring A is selected from 5-6-membered heteroaryl groups and phenyl groups; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S.

[0021] In one embodiment, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R1 is selected from -H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy groups, halogens, and cyano groups.

[0022] In one implementation, R1 is selected from C. 1-6 Alkyl, C 3-4 cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy groups, halogens.

[0023] In one implementation, R1 is selected from C.1-4 Alkyl, cyclopropyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy groups, halogens.

[0024] In one embodiment, R1 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, -F, -Cl, -Br, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, deuterated hexyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated butoxy, deuterated pentoxy, and deuterated hexoxy.

[0025] In one embodiment, R1 is selected from methyl, methoxy, -CD3, -O-CD3, -F, -Cl, and -Br.

[0026] In one embodiment, R1 is selected from methyl.

[0027] In one embodiment, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R2 is selected from -H, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C2-6 ynyl.

[0028] In one implementation, R2 is selected from -H, C 1-6 Alkyl, C 3-4 cycloalkyl, C 1-6 Haloalkyl, C 1-6 deuterated alkyl,

[0029] In one implementation, R2 is selected from -H, C 1-4 Alkyl, C 1-4 Deuterated alkyl, cyclopropyl, C 1-4 Halogenated alkyl groups.

[0030] In one embodiment, R2 is selected from -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, deuterated hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, or halohexyl.

[0031] In one embodiment, R2 is selected from -H, methyl, ethyl, -CHF2, -CF3, -CH2CH2F, and -CD3.

[0032] In one embodiment, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, ... The substituents of the phenyl group are selected from halogens, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy group, -CN; the substituent of the pyridyl group is selected from halogens, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy groups, -CN.

[0033] In one embodiment, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl group are selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy group, -CN; the substituent of the pyridyl group is selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -CN.

[0034] In one embodiment, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl group are selected from -F, -Cl, -Br, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 The pyridyl group is selected from -F, -Cl, -Br, and C. 1-4 alkyl.

[0035] In one implementation, R3 is selected from...

[0036] In one implementation, R3 is selected from...

[0037] In one implementation, R3 is selected from...

[0038] In one implementation, R3 is selected from...

[0039] In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R4 is selected from substituted or unsubstituted C4.1-8 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted C 6-9 Aryl, C 2-6 acetylinyl

[0040] The C 1-8 The alkyl substituents are selected from -H, deuterium, halogen, -OH, -COOH, and -C(O)NR. a R b substituted or unsubstituted 5-6 aryl groups, C 3-6 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclic alkyl, C 1-6 Alkoxy, C 2-6 The 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the 5-6-membered heterocyclic alkyl group contains 1 to 2 heteroatoms selected from N, O, and S; the -CH2- on the 5-6-membered heterocyclic alkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituents of the 5-6-membered heteroaryl group are selected from halogens, C... 1-6 Alkyl, -NH2, -OH, -CF3; the substituents of the 5-6 membered heterocyclic alkyl group are selected from -OH, C 1-6 Alkyl; R a R b Each is independently selected from -H, C 1-4 alkyl;

[0041] The C 3-12 The -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-12 The substituents of the cycloalkyl group are selected from -H, deuterium, and C. 1-6 Hydroxyalkyl, -C(O)NH2, -OH, -COOH, halogen, substituted or unsubstituted 5-6 membered heteroaryl, -CF3, C 1-6 Alkyl, -NH2, C 1-6 Alkoxy, -NHC(O)CH3, -NHS(O)2CH3, C 2-6 The 5-6 membered heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-6 Haloalkyl, C 1-6 alkyl;

[0042] The -CH2- atom on the 4-10 membered heterocyclic alkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-10 membered heterocyclic alkyl ring contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-10 membered heterocyclic alkyl ring are selected from C. 1-6 Hydroxyalkyl, -CF3, -OH, -COOH, C 1-6 Alkyl, C 1-6 Carbonyl, -S(O)2CH3, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 2-6 The alkynyl group or halogen-substituted phenyl group; the 4-6 membered heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S;

[0043] The 5-8-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 5-8-membered heteroaryl group are selected from C. 1-6 Alkyl, halogen, -COOH, -CF3;

[0044] The C 6-9 The substituents of the aryl group are selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -COOH, -B(OH)2.

[0045] In one implementation, R4 is selected from C. 1-8 Alkyl, substituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C 6-9 Aryl, C 2-6 acetylinyl

[0046] The C 1-6 The alkyl substituents are selected from -H, deuterium, halogen, -OH, -C(O)NH2, substituted or unsubstituted 5-6 membered heteroaryl groups, C 3-6 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclic alkyl, C 1-4 Alkoxy, C 2-4 The 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the 5-6-membered heterocyclic alkyl group contains 1 to 2 heteroatoms selected from N, O, and S; the -CH2- on the 5-6-membered heterocyclic alkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituents of the 5-6-membered heteroaryl group are selected from halogens, C... 1-4 Alkyl, -NH2, -OH, -CF3; the substituents of the 5-6 membered heterocyclic alkyl group are selected from -OH, C1-4 alkyl;

[0047] The C 3-10 The -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-10 The substituents of the cycloalkyl group are selected from -H, deuterium, and C. 1-4 Hydroxyalkyl, -C(O)NH2, -OH, halogen, substituted or unsubstituted 5-6 membered heteroaryl, -CF3, C 1-4 Alkyl, -NH2, C 1-4 Alkoxy, -NHC(O)CH3, -NHS(O)2CH3, C 2-4 The 5-6 membered heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-4 Haloalkyl, C 1-4 alkyl;

[0048] The -CH2- atom on the 4-10 membered heterocyclic alkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-10 membered heterocyclic alkyl ring contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-10 membered heterocyclic alkyl ring are selected from C. 1-4 Hydroxyalkyl, -CF3, -OH, C 1-4 Alkyl, C 1-4 Carbonyl, -S(O)2CH3, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 2-4 The alkynyl group or halogen-substituted phenyl group; the 4-6 membered heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S;

[0049] The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-4 Alkyl, halogen, -CF3;

[0050] The C 6-9 The substituents of the aryl group are selected from halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl group, -B(OH)2.

[0051] In one implementation, R4 is selected from C. 1-8 Alkyl, substituted C 1-6 alkyl, Replacement C 3-7 Cycloalkyl, substituted 4-6 membered heterocyclic alkyl, Substituted or unsubstituted 5-6 membered heteroaryl groups, substituted or unsubstituted phenyl groups, C 2-4 acetylinyl

[0052] The C 1-6 The alkyl substituents are selected from -H, deuterium, -F, -Cl, -Br, -OH, -C(O)NH2, cyclopropyl, methoxy, ethynyl, etc.

[0053] The C 3-7 The substituents of the cycloalkyl group are selected from -H, deuterium, hydroxymethyl, -C(O)NH2, -OH, -F, -Cl, -Br, -CF3, methyl, ethyl, -NH2, methoxy, -NHC(O)CH3, -NHS(O)2CH3, ethynyl;

[0054] The 4-6 membered heterocyclic alkyl group contains 1 to 2 heteroatoms selected from N, O, and S; the substituents of the 4-6 membered heterocyclic alkyl group are selected from C. 1-4 Hydroxyalkyl, -CF3, -OH, C 1-4 Alkyl, C 1-4 carbonyl group, -S(O)2CH3, Pyridyl, pyrimidinyl, thiophenyl, pyrazinyl, pyridazinyl, C 2-4 Alkyne- or chlorinated phenyl groups;

[0055] The 5-6 membered heteroaryl group is selected from pyridyl, thiazolyl, isoxazolyl, and pyrazolyl; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-4 Alkyl, halogen, -CF3;

[0056] The substituents of the phenyl group are selected from halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl group, -B(OH)2.

[0057] In one implementation, R4 is selected from tert-butyl,

[0058] In one implementation, R4 is selected from tert-butyl,

[0059] In one implementation, R4 is selected from tert-butyl,

[0060] In one implementation, R4 is selected from tert-butyl,

[0061] In one implementation, R4 is selected from tert-butyl,

[0062] In one embodiment, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in Formula V:

[0063]

[0064] The definitions of R1, R2, and R3 refer to the aforementioned definitions.

[0065] In one embodiment, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in Formula Va:

[0066]

[0067] The definitions of R2 and R3 refer to the aforementioned definitions.

[0068] In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in formula Vaa:

[0069]

[0070] The definitions of R2 and R3 refer to the aforementioned definitions.

[0071] In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in Formula Vab:

[0072]

[0073] The definitions of R2 and R3 refer to the aforementioned definitions.

[0074] In one embodiment, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in Formula VI:

[0075]

[0076] The definition of R4 references the aforementioned definition.

[0077] In one embodiment, the above-described compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in Formula VII:

[0078]

[0079] The definition of R4 references the aforementioned definition.

[0080] In one embodiment, the above-described compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure shown in Formula VIII:

[0081]

[0082] The definition of R4 references the aforementioned definition.

[0083] In one embodiment, the present invention provides a compound of formula (1), or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0084]

[0085] Among them, R 11 Selected from -H, C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Deuterated alkoxy groups, halogens, and cyano groups;

[0086] R 12 Selected from -H, C 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Haloalkyl, C 1-8 Deuterated alkyl, C 1-8 Hydroxyalkyl, C2-8 ynyl;

[0087] R 13 C14 cells selected from unsubstituted or substituted with one or more identical or different substituents 6-10 aryl, unsubstituted, or 5-10 membered heteroaryl groups substituted with one or more identical or different substituents; said 5-10 membered heteroaryl group contains one to three heteroatoms selected from N, O, and S; said C 6-10 The substituents of the aryl group are selected from halogens, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 The substituents of the 5-10 membered heteroaryl group are selected from halogens and C. 1-8Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, -CN;

[0088] R 14 Selected from C 2-8 C16, alkynyl group, unsubstituted or substituted with one or more identical or different substituents. 6-10 aryl, unsubstituted or substituted with one or more identical or different substituents C 5-12 Bridged cycloalkyl groups, unsubstituted or substituted with one or more identical or different substituents, 5-10 membered heteroaryl groups The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the C 6-10 The substituents of the aryl group are selected from halogens, -B(OH)2, C 1-8 Alkyl, C 1-8 Halogenated alkyl group, -COOH; the substituents of the 5-10 membered heteroaryl group are selected from halogens, C 1-8 Alkyl, -COOH, -C(O)NR e R f C 1-8 Halogenated alkyl; the C 5-12 The substituents of the bridged cycloalkyl group are selected from -OH;

[0089] R 15 R 16 Each is independently selected from -H, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl; or R 15 R 16 The carbon atoms bonded to them form C atoms selected from unsubstituted or substituted with one or more identical or different substituents. 3-12 Cycloalkyl, unsubstituted or substituted with one or more identical or different substituents, 3-10 membered heterocyclic alkyl; the 3-10 membered heterocyclic alkyl contains 1 to 3 heteroatoms selected from N, O and S; the C 3-12 The substituents of the cycloalkyl group are selected from deuterium, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkyl, -C(O)NR e R f -NR e R f -COOR e halogen, -OH, C 1-8 alkoxy groups; the substituents of the 3-10 membered heterocyclic alkyl groups are selected from C 1-8 Hydroxyalkyl, C 1-8 Halogenated alkyl groups, -OH, -COOR e-C(O)NR e R f C 1-8 Alkyl, -C(O)R e -S(O)2R g ;

[0090] R 17 Selected from -H, deuterium, halogen, -OH, -CN, -NR e R f -COOR e -C(O)NR e R f C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 2-8 alkynyl group, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy C 1-8 Alkyl, C 3-8 The 5-6 membered heteroaryl group is composed of a cycloalkyl group, an unsubstituted 5-6 membered heteroaryl group or a substituted 4-6 membered heterocycloalkyl group or a substituted 4-6 membered heterocycloalkyl group; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S; the 4-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-8 Alkyl, halogen, -NR e R f -OH, C 1-8 Haloalkyl, C 1-8 Deuterated alkyl; the substituents of the 4-6 membered heterocyclic alkyl group are selected from C 1-8 Alkyl, -OH, -S(O)2R g ;

[0091] R e R f R g Each is independently selected from -H, C 1-4 alkyl.

[0092] In some embodiments, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R 11 Selected from -H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy groups, halogens, and cyano groups.

[0093] In some implementation schemes, R 11 Selected from C 1-6 Alkyl, C 3-4 cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy groups, halogens.

[0094] In some implementation schemes, R 11 Selected from C 1-4 Alkyl, cyclopropyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy groups, halogens.

[0095] In some implementation schemes, R 11 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, -F, -Cl, -Br, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, deuterated hexyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated butoxy, deuterated pentoxy, and deuterated hexoxy.

[0096] In some implementation schemes, R 11 Selected from methyl, methoxy, -CD3, -O-CD3, -F, -Cl, -Br, -CF3.

[0097] In some implementation schemes, R 11 Selected from methyl, -CD3, -F, -Cl, -Br, -CF3.

[0098] In some implementation schemes, R 11 Selected from methyl.

[0099] In some embodiments, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R 12 Selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C2-6 ynyl.

[0100] In some implementation schemes, R 12 Selected from -H, C 1-6 Alkyl, C 3-4 cycloalkyl, C 1-6 Haloalkyl, C 1-6 deuterated alkyl,

[0101] In some implementation schemes, R 12 Selected from -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, deuterated hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, or halohexyl.

[0102] In some implementation schemes, R 12 Selected from -H, C 1-4 Alkyl, C 1-4 Deuterated alkyl, cyclopropyl, C 1-4 Halogenated alkyl groups.

[0103] In some implementation schemes, R 12 Selected from -H, methyl, ethyl, -CHF2, -CF3, -CH2CH2F, -CD3.

[0104] In some implementation schemes, R 12 Selected from -H, methyl, -CHF2, -CF3, -CD3.

[0105] In some implementation schemes, R 12 Selected from methyl, -CD3.

[0106] In some implementation schemes, R 12 Selected from methyl.

[0107] In some embodiments, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R 13 Selected from unsubstituted or substituted phenyl groups, and unsubstituted or substituted pyridyl groups, or substituted with one or more identical or different substituents. The substituents of the phenyl group are selected from halogens, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy group, -CN; the substituent of the pyridyl group is selected from halogens, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy groups, -CN.

[0108] In some implementation schemes, R 13 Selected from unsubstituted phenyl groups or those substituted with one, two, three, or four identical or different substituents, and unsubstituted pyridyl groups or those substituted with one, two, three, or four identical or different substituents. The substituents of the phenyl group are selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy group, -CN; the substituent of the pyridyl group is selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -CN.

[0109] In some implementation schemes, R 13 Selected from unsubstituted phenyl groups or those substituted with one, two, or three identical or different substituents, and unsubstituted pyridyl groups or those substituted with one, two, or three identical or different substituents. The substituents of the phenyl group are selected from -F, -Cl, -Br, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 The pyridyl group is selected from -F, -Cl, -Br, and C. 1-4 alkyl.

[0110] In some implementation schemes, R 13 Selected from

[0111] In some implementation schemes, R 13 Selected from

[0112] In some implementation schemes, R 13 Selected from

[0113] In some implementation schemes, R 13 Selected from

[0114] In some implementation schemes, R 13 Selected from

[0115] In some embodiments, in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, R 14 Selected from C 2-6 Alkyne, unsubstituted or substituted phenyl groups with one or more identical or different substituents, C14 unsubstituted or substituted C24 with one or more identical or different substituents 5-10 Bridged cycloalkyl, unsubstituted or pyridyl groups substituted with one or more identical or different substituents, The substituents of the phenyl group are selected from halogens, -B(OH)2, C 1-6 Alkyl, C 1-6Halogenated alkyl group, -COOH; the substituent of the pyridyl group is selected from halogens, C 1-6 Alkyl, -COOH, -C(O)NR e R f C 1-6 Halogenated alkyl; the C 5-10 The substituents of the bridged cycloalkyl group are selected from -OH;

[0116] R 15 R 16 Each is independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl; or R 15 R 16 The carbon atoms bonded to them form C atoms selected from unsubstituted or substituted with one or more identical or different substituents. 3-10 Cycloalkyl, unsubstituted or substituted with one or more identical or different substituents, 3-8 membered heterocyclic alkyl; the 3-8 membered heterocyclic alkyl contains one or two heteroatoms selected from N, O and S; the C 3-10 The substituents of the cycloalkyl group are selected from deuterium, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, -C(O)NR e R f -NR e R f -COOR e halogen, -OH, C 1-6 alkoxy groups; the substituents of the 3-8 membered heterocyclic alkyl groups are selected from C10. 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -OH, -COOR e -C(O)NR e R f C 1-6 Alkyl, -C(O)R e -S(O)2R g ;

[0117] R 17 Selected from -H, deuterium, halogen, -OH, -CN, -NR e R f -COOR e -C(O)NR e R f C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C1-6 Alkoxy C 1-6 Alkyl, C 3-6 The 5-6 membered heteroaryl group is composed of a cycloalkyl group, an unsubstituted 5-6 membered heteroaryl group or a 4-6 membered heterocycloalkyl ... 1-6 Alkyl, halogen, -NR e R f -OH, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl; the substituents of the 4-6 membered heterocyclic alkyl group are selected from C 1-6 Alkyl, -OH, -S(O)2R g ;

[0118] R e R f R g Each is independently selected from -H, C 1-4 alkyl.

[0119] In some implementation schemes, R 14 Selected from C 2-6 Alkyne, unsubstituted or substituted phenyl groups with one or more identical or different substituents, C14 unsubstituted or substituted C24 with one or more identical or different substituents 5-10 Bridged cycloalkyl, unsubstituted or pyridyl groups substituted with one or more identical or different substituents, The substituents of the phenyl group are selected from halogens, -B(OH)2; the substituents of the pyridyl group are selected from halogens; the C 5-10 The substituents of the bridged cycloalkyl group are selected from -OH;

[0120] R 15 R 16 Each is independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl; or R 15 R 16 The carbon atoms bonded to them form C atoms selected from unsubstituted or substituted with one or more identical or different substituents. 3-10 Cycloalkyl, unsubstituted or substituted with one or more identical or different substituents, 3-8 membered heterocyclic alkyl; the 3-8 membered heterocyclic alkyl contains one or two heteroatoms selected from N, O and S; the C 3-10 The substituents of cycloalkyl groups are selected from halogens, -OH, C. 1-6 alkoxy groups; the substituents of the 3-8 membered heterocyclic alkyl groups are selected from C10.1-6 Alkyl, -C(O)R e -S(O)2R g ;

[0121] R 17 Selected from -H, -CN, -C(O)NR e R f C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 The 5-6 membered heteroaryl group is composed of a cycloalkyl group, an unsubstituted 5-6 membered heteroaryl group or a 4-6 membered heterocycloalkyl ... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl; the substituents of the 4-6 membered heterocyclic alkyl group are selected from C 1-6 Alkyl group, -OH group;

[0122] R e R f R g Each is independently selected from -H, C 1-4 alkyl.

[0123] In some implementation schemes, R 14 Selected from C 2-4 Alkyne, unsubstituted or phenyl groups substituted with one, two or three identical or different substituents, Unsubstituted or substituted with one, two, or three identical or different substituents, pyridyl The substituents of the phenyl group are selected from halogens and -B(OH)2; the substituents of the pyridyl group are selected from halogens.

[0124] R 15 R 16 Each is independently selected from -H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl; or R 15 R 16 The carbon atoms bonded to them form C atoms selected from unsubstituted or substituted with one, two, or three identical or different substituents. 3-8Cycloalkyl, unsubstituted or substituted with one, two or three identical or different substituents, 3-8 membered heterocyclic alkyl; the 3-8 membered heterocyclic alkyl contains one or two heteroatoms selected from N, O and S; the C 3-8 The substituents of cycloalkyl groups are selected from halogens, -OH, C. 1-4 alkoxy groups; the substituents of the 3-8 membered heterocyclic alkyl groups are selected from C10. 1-4 Alkyl, -C(O)R e -S(O)2R g ;

[0125] R 17 Selected from -H, -CN, -C(O)NR e R f C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 The 5-6 membered heteroaryl group is a cycloalkyl group, unsubstituted or substituted with one, two or three identical or different substituents; the 5-6 membered heteroaryl group contains one to three heteroatoms selected from N and O; the 5-6 membered heteroaryl group contains one to two heteroatoms selected from N and O; the substituents of the 5-6 membered heteroaryl group are selected from C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl; the substituents of the 5-6 membered heterocyclic alkyl group are selected from C 1-4 Alkyl group, -OH group;

[0126] R e R f R g Each is independently selected from -H, C 1-4 alkyl.

[0127] In some implementation schemes, R 14 Selected from C 2-4 Alkyne, unsubstituted or phenyl groups substituted with one or two identical or different substituents, Unsubstituted or substituted pyridyl groups, or those substituted with one or two identical or different substituents. The substituents of the phenyl group are selected from -F, -Cl, -Br, -B(OH)2; the substituents of the pyridyl group are selected from -F, -Cl, -Br;

[0128] R 15 R 16Each is independently selected from -H, methyl, ethyl, isopropyl, tert-butyl, -CF3, -CH2F, hydroxymethyl; or R 15 R 16 The carbon atoms bonded to them form C atoms selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexyl groups, substituted with one or two identical or different substituents. 4-7 Cycloalkyl, unsubstituted or substituted with one or two identical or different substituents, 4-8 membered heterocyclic alkyl; the 4-8 membered heterocyclic alkyl contains one heteroatom selected from N, O and S; the C 4-7 The substituents of the cycloalkyl group are selected from -F, -Cl, -Br, -OH, methoxy, and ethoxy; the substituents of the 4-8 membered heterocyclic alkyl group are selected from methyl, ethyl, and -C(O)R. e -S(O)2R g ;

[0129] R 17 Selected from -H, -CN, -C(O)NR e R f , methyl, ethyl, -CF3, ethynyl, C 1-4 Hydroxyalkyl, methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, unsubstituted or substituted with one substituent, 5-6 membered heterocyclic alkyl group; wherein the 5-membered heterocyclic alkyl group contains 2 to 3 heteroatoms selected from N; wherein the 5-6 membered heterocyclic alkyl group contains 1 to 2 heteroatoms selected from O; wherein the substituents of the 5-membered heterocyclic alkyl group are selected from methyl, ethyl, isopropyl, -CF3, -CD3; wherein the substituents of the 5-6 membered heterocyclic alkyl group are selected from methyl, ethyl, -OH;

[0130] R e R f R g Each is independently selected from -H, methyl, and ethyl.

[0131] In some implementation schemes, R 14 Selected from tert-butyl, isopropyl, Cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,

[0132] In some implementation schemes, R 14 Selected from tert-butyl, isopropyl, Cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,

[0133] In some implementation schemes, R 14 Selected from Cyclobutyl,

[0134] In some implementation schemes, R 14 Selected from

[0135] In some implementation schemes, R 14 Selected from

[0136] In some implementation schemes, R 14 Selected from

[0137] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (2):

[0138]

[0139] Among them, R 11 R 12 and R 13 The definition is as described above.

[0140] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (2-A):

[0141]

[0142] Among them, R 13 The definition is as described above.

[0143] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (2-Aa):

[0144]

[0145] Among them, R 13 The definition is as described above.

[0146] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (2-Ab):

[0147]

[0148] Among them, R 13 The definition is as described above.

[0149] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (3):

[0150]

[0151] Among them, R 14 The definition is as described above.

[0152] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (4):

[0153]

[0154] Among them, R 14 The definition is as described above.

[0155] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (5):

[0156]

[0157] Among them, R 14 The definition is as described above.

[0158] In some embodiments, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, has the structure described in formula (6):

[0159]

[0160] Among them, R 13 R 14 The definition is as described above.

[0161] In one embodiment, the compound of the present invention, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, is selected from the following structural formulas:

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185] In this invention, when R4 is selected from substituted or unsubstituted 4-14-membered heterocyclic alkyl groups or 4-10-membered heterocyclic alkyl groups, it refers to the presence of 4-14 or 4-10 ring atoms on the ring, where the ring atoms are carbon atoms and heteroatoms. 4-14-membered or 4-10-membered heterocyclic alkyl groups include monocyclic, bicyclic, and tricyclic groups; bicyclic or tricyclic groups include fused rings, spirocyclic, and bridged rings. If it is a bicyclic or tricyclic group, the heteroatoms can be on any of the rings, or simultaneously on two or three rings.

[0186] In this invention, R 15 R 16When the carbon atoms connected to them form unsubstituted or substituted 3-10, 3-8, or 4-8 heterocyclic alkyl groups with one or more identical or different substituents, the ring has 3-10, 3-8, or 4-8 ring atoms, which are carbon atoms and heteroatoms. 3-10, 3-8, or 4-8 heterocyclic alkyl groups include monocyclic, bicyclic, and tricyclic groups. Bicyclic or tricyclic groups include fused rings, spirocyclic, and bridged rings.

[0187] In this invention, R4 is selected from substituted or unsubstituted C. 3-14 cycloalkyl, C 3-12 cycloalkyl or C 3-10 When cycloalkyl is used, it refers to a ring with 3-14, 3-12, or 3-10 ring atoms, where the ring atoms are carbon atoms. C 3-14 cycloalkyl, C 3-12 cycloalkyl or C 3-10 Cycloalkyl groups include monocyclic, bicyclic, and tricyclic groups, with bicyclic or tricyclic groups including fused rings, spirocyclic, and bridged rings.

[0188] In this invention, R 15 R 16 The carbon atoms bonded to them form unsubstituted or substituted carbon atoms with one or more identical or different substituents. 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-8 cycloalkyl or C 4-7 When cycloalkyl is used, it refers to the presence of 3-12, 3-10, 3-8, or 4-7 ring atoms, where the ring atoms are carbon atoms. (C) 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-8 cycloalkyl or C 4-7 Cycloalkyl groups include monocyclic, bicyclic, and tricyclic groups, with bicyclic or tricyclic groups including fused rings, spirocyclic, and bridged rings.

[0189] Technical terms of this invention:

[0190] In this invention, the term "optional" means that it may or may not be replaced by the subsequently described portion. For example, "the -CH2- on the 5- or 6-membered heterocyclic alkyl ring may be optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-" can be understood as "the -CH2- on the 5- or 6-membered heterocyclic alkyl ring may be replaced by -C(=O)-, -C(=S)-, or -S(=O)2-", or it can be understood as "the -CH2- on the 5- or 6-membered heterocyclic alkyl ring is not replaced".

[0191] In this invention, the term "substituted" means that an atom or group of atoms formally replaces hydrogen and is attached to another group as a "substituent". Unless otherwise stated, the term "substituted" refers to any degree of substitution where such substitution is permissible, such as monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. It should be understood that substitution at a specified atom is limited by the valence of the atom. It should be understood that substitution at a specified atom produces a chemically stable molecule.

[0192] In this invention, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be straight-chain or branched. The term "C 1-10 "Alkyl" refers to an alkyl group having 1 to 10 carbon atoms. An alkyl group formally corresponds to an alkane where a CH bond is replaced by a point where the alkyl group connects to the rest of the compound. In some embodiments, the alkyl group contains 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms. Examples of alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, dibutyl; and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc.

[0193] In this invention, the term "alkynyl" used alone or in combination with other terms refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. Formally, an alkynyl corresponds to an alkyne where a CH bond is replaced by an alkyl group at the junction with the rest of the compound. The term "C2-8 alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0194] In this invention, the term "alkoxy" used alone or in combination with other terms refers to a group having the formula -O-alkyl, wherein the term "alkyl" is as defined above. The term "C" 1-8 "Alkoxy" refers to an alkoxy group whose alkyl group has 1 to 8 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. In some embodiments, the alkyl group has 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms.

[0195] In this invention, the term "halogenated" or "halogen" used alone or in combination with other terms refers to F, Cl, Br, and I. In some embodiments, the term "halogenated" refers to a halogen atom selected from F, Cl, or Br.

[0196] In this invention, the term "haloalkyl" or "haloalkoxy" used alone or in combination with other terms refers to an alkyl or alkoxy group substituted with one or more halogens, wherein the terms "halogen," "alkyl," and "alkoxy" are as defined above.

[0197] In this invention, the term "deuterated alkyl" used alone or in combination with other terms refers to an alkyl group substituted with one or more deuterium atoms, wherein the term "alkyl" is as defined above.

[0198] In this invention, the term "hydroxyalkyl" used alone or in combination with other terms refers to an alkyl group substituted with one or more hydroxyl groups, wherein the term "alkyl" is as defined above.

[0199] In this invention, the term "heteroatoms," used alone or in combination with other terms, includes B, P, S, O, and N.

[0200] In this invention, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having two fused rings). The term "C 6-10 "Aryl" refers to an aryl group having 6 to 10 cyclic carbon atoms. Aryl groups include, for example, phenyl, naphthyl, indenyl, and indene. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0201] In this invention, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from B, P, S, O, and N. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, any cyclic N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5 to 14 ring atoms, including a carbon atom and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, the heteroaryl has 5 to 10 ring atoms, including a carbon atom and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from S, O, and N. In some embodiments, the heteroaryl is a five- or six-membered heteroaryl ring. In other embodiments, the heteroaryl group is an octa-, 9-, or 10-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrroleyl, pyrazolyl, azole, oxazolyl, thiazolyl, imidazoleyl, furanyl, thiopheneyl, quinolinyl, isoquinolinyl, naphthidyl (including 1,2-naphthidine, 1,3-naphthidine, 1,4-naphthidine, 1,5-naphthidine, 1,6-naphthidine, 1,7-naphthidine, 1,8-naphthidine, 2,3-naphthidine, and 2,6-naphthidine), indoleyl, benzothiopheneyl, benzofuranyl, benzoisoxazolyl, imidazole[1,2-b]thiazolyl, purineyl, etc.

[0202] In this invention, the term "cycloalkyl" used alone or in combination with other terms refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cycloalkyl groups. The term "C"... 3-8 "Cycloalkyl" or "C" 3-14 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 or 3 to 14 ring-member carbon atoms, respectively. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 cyclic carbons (C atoms). 3-14 In some embodiments, the cycloalkyl group has 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C10. 3-8Monocyclic cycloalkyl groups. Cycloalkyl groups also include cyclohexylene groups. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norcamphenyl, norpinel, norcarelyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0203] In this invention, the term "heterocyclic alkyl" used alone or in combination with other terms refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from B, P, N, S, and O, and having 4 to 10, 4 to 7, or 4 to 6 ring members. The term "heterocyclic alkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocyclic alkyl groups. Heterocyclic alkyl groups can include monocyclic or bicyclic (e.g., having two fused or bridging rings) ring systems. In some embodiments, a heterocyclic alkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from N, S, and O. Heterocyclic alkyl groups can be linked via cyclic carbon atoms or cyclic heteroatoms. Examples of heterocyclic alkyl groups include azirrobutyl, azirroheptyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and scopolamine.

[0204] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0205] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0206] An important consideration in planning synthetic routes in this field is selecting suitable protecting groups for reactive functional groups (such as amino groups in this application). For example, reference can be made to Chem. Commun., 2019, 55, 7331-7334. All references cited in this application are incorporated herein by reference in their entirety. Alternatively, a combination of synthetic methods known in the art and the methods described in this invention can be used. The products obtained from each reaction step are obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, and chromatographic separation. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to literature (such as those provided by SciFinder) or purchased.

[0207] In some embodiments, the compound of general formula (I) (i.e., G) of this application can be prepared by those skilled in the art of organic synthesis using standard methods in the art via the following route:

[0208] Route 1:

[0209]

[0210] Step 1: The compound shown in Formula A and the compound shown in Formula B undergo amine-ester exchange under alkaline conditions to obtain the compound of Formula C;

[0211] Step 2: The compound shown in Formula C and the compound shown in Formula D undergo a Friedel-Crafts reaction under Lewis acid conditions to obtain the compound of Formula E.

[0212] Step 3: The compound shown in formula E reacts with NFSI under the catalysis of nitrogen oxides to undergo a CH amination reaction to obtain the compound of formula F;

[0213] Step 4: Under acidic conditions, the protecting group of the compound shown in formula F is removed to obtain the compound of formula G;

[0214] Wherein, R1, R2, R3 and R4 are as defined in this invention.

[0215] Route 2:

[0216]

[0217] Step 1: The compound shown in Formula C and the compound shown in Formula D-1 undergo a Friedel-Crafts reaction under Lewis acid conditions to give the compound shown in Formula J.

[0218] Step 2: The compound shown in formula J undergoes a hydrolysis reaction under alkaline conditions to obtain the compound shown in formula K;

[0219] Step 3: The compound shown in formula K and the compound shown in formula B-1 undergo a condensation reaction to obtain the compound shown in formula E.

[0220] Step 4: The compound shown in Formula E reacts with NFSI under the catalysis of nitrogen oxides to undergo a CH amination reaction to obtain the compound shown in Formula F;

[0221] Step 5: Under acidic conditions, the protecting group of the compound shown in formula F is removed to obtain the compound shown in formula G;

[0222] Wherein, R1, R2, R3 and R4 are as defined in this invention.

[0223] Route 3:

[0224]

[0225] Step 1: The compound shown in formula J reacts with NFSI under the catalysis of nitrogen oxides to undergo a CH amination reaction to obtain the compound shown in formula L;

[0226] Step 2: Under acidic conditions, the protecting group of the compound shown in formula L is removed to obtain the compound shown in formula M;

[0227] Step 3: The compound shown in formula M undergoes a hydrolysis reaction under alkaline conditions to obtain the compound shown in formula N;

[0228] Step 4: The compound shown in Formula N and the compound shown in Formula B-1 undergo a condensation reaction to obtain the compound shown in Formula G.

[0229] Wherein, R1, R2, R3 and R4 are as defined in this invention.

[0230] In some embodiments, the compound of general formula (1) of this application (i.e., Ga) can be prepared by those skilled in the art of organic synthesis using standard methods in the art via the following route:

[0231] Route 1:

[0232]

[0233] Step 1: The compound represented by formula Aa and the compound represented by formula Ba undergo amine-ester exchange under alkaline conditions to obtain the compound represented by formula Ca.

[0234] Step 2: The compound represented by formula Ca and the compound represented by formula Da undergo a Friedel-Crafts reaction under Lewis acid conditions to obtain the compound of formula Ea.

[0235] Step 3: The compound shown in formula Ea reacts with NFSI under the catalysis of nitrogen oxides to undergo a CH amination reaction to obtain the compound of formula Fa;

[0236] Step 4: Under acidic conditions, the protecting group of the compound represented by formula Fa is removed to obtain the compound of formula Ga;

[0237] Among them, R11 R 12 R 13 and R 14 As defined in this invention.

[0238] Route 2:

[0239]

[0240] Step 1: The compound shown in formula Ca and the compound shown in formula D-2 undergo a Friedel-Crafts reaction under Lewis acid conditions to give the compound shown in formula Ja.

[0241] Step 2: The compound represented by formula Ja undergoes a hydrolysis reaction under alkaline conditions to obtain the compound represented by formula Ka;

[0242] Step 3: The compound shown in formula Ka and the compound shown in formula B-2 undergo a condensation reaction to obtain the compound shown in formula Ea.

[0243] Step 4: The compound shown in formula Ea reacts with NFSI under the catalysis of nitrogen oxides to undergo a CH amination reaction to obtain the compound shown in formula Fa;

[0244] Step 5: Under acidic conditions, the protecting group of the compound represented by formula Fa is removed to obtain the compound represented by formula Ga;

[0245] Among them, R 11 R 12 R 13 and R 14 As defined in this invention.

[0246] Route 3:

[0247]

[0248] Step 1: The compound shown in formula Ja reacts with NFSI under the catalysis of nitrogen oxides to undergo a CH amination reaction to obtain the compound shown in formula La;

[0249] Step 2: The compound shown in formula La is reacted with acidic conditions to remove the protecting group, yielding the compound shown in formula Ma;

[0250] Step 3: The compound shown in formula Ma undergoes a hydrolysis reaction under alkaline conditions to obtain the compound shown in formula Na;

[0251] Step 4: The compound represented by formula Na undergoes a condensation reaction with the compound represented by formula B-2 to obtain the compound represented by formula Ga.

[0252] Among them, R 11 R 12 R 13 and R14 As defined in this invention.

[0253] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), (V), (Va), (Vaa), (Vab), (VI), (VII), (VIII), (1), (2), (2-A), (2-Aa), (2-Ab), (3), (4), (5) or (6), a prodrug thereof, a solvate, a crystal form, a pharmaceutically acceptable salt, a stereoisomer or tautomer, and a pharmaceutically acceptable auxiliary ingredient.

[0254] The present invention also provides the use of compounds of formula (I), (V), (Va), (Vaa), (Vab), (VI), (VII), (VIII), (1), (2), (2-A), (2-Aa), (2-Ab), (3), (4), (5) or (6), their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers, or the above-described pharmaceutical compositions in the preparation of a medicament for use against HBV infection.

[0255] The present invention also provides a method for treating HBV infection by administering to a patient in need a compound of formula (I), (V), (Va), (Vaa), (Vab), (VI), (VII), (VIII), (1), (2), (2-A), (2-Aa), (2-Ab), (3), (4), (5) or (6), its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer or the above-described pharmaceutical composition.

[0256] The beneficial effects of this invention are:

[0257] The compounds of this invention exhibit excellent anti-HBV activity, and the exposure level in the target organ, the liver, remains at a high and stable level. They also have a longer half-life, better pharmaceutical properties, and high solubility, achieving unexpected technical effects. Detailed Implementation

[0258] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0259]

[0260] Example 1: Preparation of compound 1-d

[0261]

[0262] Step 1: Synthesis of compound 1-b

[0263] 1-a (2 g, 13.05 mmol) was added to a two-necked flask, dissolved in N,N-dimethylformamide (10 mL), and cooled to 0 °C. Under nitrogen protection, sodium hydride (1.0 g, 26.1 mmol) was added, and the mixture was stirred in an ice-water bath for 40 minutes. Iodomethane (0.97 mL, 15.67 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water (100 mL), stirred for 2 minutes, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.4 g of a pale yellow, transparent, oily product, compound 1-b. MS m / z (ESI): 167.1 [M-1] -

[0264] Step 2: Synthesis of compound 1-d

[0265] 1-b (1.2 g, 7.18 mmol) was added to a two-necked flask and dissolved in tetrahydrofuran (20 mL). Then, 1-c (1.00 mL, 10.05 mmol) was added at room temperature. Under nitrogen protection, bis(trimethylsilylaminolithium) (21.53 mL, 21.5 mmol) was added dropwise at 25 °C. After the addition was complete, the reaction mixture was allowed to react at 25 °C for approximately 1.5 hours. The reaction solution was then poured into ice water (20 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a small amount of ethyl acetate was added to the resulting solid. The mixture was then filtered through a suction funnel and washed with a small amount of ethyl acetate to give 1.3 g of a white solid, compound 1-d. MS m / z (ESI): 249.1 [M⁻¹] -

[0266] Example 2 Preparation of Compound 2

[0267]

[0268] Step 1: Synthesis of compound 2-c

[0269] 2-a (3 g, 26.53 mmol) was added to a reaction flask and dissolved in dichloromethane (18 mL). N,N-diisopropylethylamine (5.3 mL, 31.8 mmol) was then added under ice-water bath conditions, followed by dropwise addition of 2-b (3.3 mL, 29.18 mmol). After the addition was complete, the reaction was carried out at 25°C for approximately 3 hours. The reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5.6 g of a red, transparent, oily product, compound 2-c. MS m / z (ESI): 212.1 [M⁻¹] - .

[0270] Step 2: Synthesis of compound 2-d

[0271] 2-c (5.6 g, 26.27 mmol) was added to a reaction flask and dissolved in ethanol (40 mL). A solution of sodium hydroxide (3.2 g, 78.8 mmol) in water (5 mL) was added at 0 °C. The reaction was allowed to proceed for approximately 2 hours at 0 °C until completion. After filtration, the filter cake was washed with ethanol to obtain a white solid. The pH of the filtrate was adjusted to approximately 2. The ethanol was concentrated, and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the filter cakes were combined to obtain 3.2 g of a white solid, compound 2-d. MS m / z (ESI): 184.1 [M⁻¹] -

[0272] Step 3: Synthesis of compound 2-e

[0273] Add 2-d (1.3 g, 7.02 mmol) to the reaction flask, add 4 mL of thionyl chloride, heat under reflux for 1 hour, then stop the reaction and concentrate under reduced pressure to obtain 2-e for later use.

[0274] Step 4: Synthesis of compound 2-f

[0275] 1-d (0.5 g, 2 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Then, 2-e (0.61 g, 3 mmol) and aluminum trichloride (0.67 g, 5 mmol) were added under ice-water bath conditions. After reacting at room temperature for approximately 1 hour, the reaction was quenched with water. The dichloromethane was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 0.6 g of a yellow solid compound 2-f. MS m / z (ESI): 416.1 [M⁻¹] -

[0276] Step 5: Synthesis of compound 2-g

[0277] 2-F (0.4 g, 0.96 mmol), N-fluorobis(benzenesulfonamide) (0.6 g, 1.92 mmol), and 2,2,6,6-tetramethylpiperidine oxide (0.03 g, 0.19 mmol) were added to a reaction flask, dissolved in ethyl acetate (5 mL), and reacted at 50 °C for 3 hours. The residue was then concentrated and passed through a C1... 18 Column purification was performed at a ratio of 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]) to 68% (acetonitrile):32% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 0.32 g of a yellow solid product compound (2-g). MS m / z (ESI): 711.1 [M-1] -

[0278] Step 6: Synthesis of Compound 2

[0279] 2-g (0.32g, 0.45mmol) was added to a reaction flask, dissolved in dichloroethane (4mL), followed by the addition of trifluoromethanesulfonic acid (0.08mL, 0.9mmol). The mixture was heated to 80°C and stirred for 2 hours. The residue was then concentrated and passed through a C1 filter. 18 Column purification was performed using an eluent ratio of 65% (acetonitrile):35% (ultrapure water [0.005% / L formic acid]) to 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 0.08 g of a yellow solid, compound 2. MS m / z (ESI): 431.1 [MH] -

[0280] 1 H NMR (600MHz, DMSO) δ10.18(s,1H),9.20(d,J=8.8Hz,1H),7.83(ddd,J=13.8,7.8,2.0Hz,1H),7.4 2–7.37(m,2H),7.32(s,2H),4.71–4.65(m,1H),3.39(s,3H),2.10(s,3H),1.29(d,J=7.1Hz,3H).

[0281] Example 3 Preparation of Compound 3

[0282]

[0283] Step 1: Synthesis of compound 3-a

[0284] 1-d (0.5 g, 2 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Then, 2-b (0.68 g, 5 mmol) and aluminum trichloride (0.8 g, 6 mmol) were added under ice-water bath conditions. After reacting at room temperature for approximately 1 hour, the reaction was quenched with water. The dichloromethane was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 0.56 g of a brown solid compound 3-a. MS m / z (ESI): 349.1 [M⁻¹] -

[0285] Step 2: Synthesis of compound 3-b

[0286] 3-a (0.56 g, 1.59 mmol) was added to a reaction flask and dissolved in ethanol (5 mL). A solution of sodium hydroxide (0.19 g, 4.8 mmol) in water (1 mL) was added at 0 °C. After reacting for approximately 2 hours at 0 °C, a large amount of solid was produced. The reaction was stopped, and the solid was filtered. The remaining solution was washed with ethyl acetate (2 x 20 mL), and the organic layer was separated. The pH of the aqueous phase was adjusted to approximately 2, and the solution was concentrated. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The products were combined and further concentrated under reduced pressure to obtain 0.313 g of a red solid compound, 3-b. MS m / z (ESI): 321.1 [M⁻¹] -

[0287] Step 3: Synthesis of compound 3-d

[0288] 3-b (0.31 g, 0.97 mmol) was added to a reaction flask, dissolved in N,N-dimethylformamide (15 mL), followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.96 g, 2.5 mmol) and N,N-diisopropylethylamine (0.48 mL, 2.9 mmol). Finally, 3-c (0.07 mL, 1.07 mmol) was added. The reaction was carried out overnight at 25 °C, and the reaction was quenched with water (50 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. The eluent ratio was petroleum ether:ethyl acetate = 7%:93%–12%:88%. After purification by concentrated under reduced pressure, 0.21 g of the pale yellow compound 3-d was finally obtained. MS m / z (ESI): 358.1 [M-1] -

[0289] Step 4: Synthesis of compound 3-e

[0290] 3-d (0.19 g, 0.53 mmol), N-fluorobis(benzenesulfonamide) (1.66 g, 5.26 mmol), and 2,2,6,6-tetramethylpiperidine oxide (0.016 g, 0.11 mmol) were added to a reaction flask, dissolved in ethyl acetate (5 mL), and reacted at 50 °C for 5 hours. The residue was concentrated and purified by silica gel column chromatography with an eluent ratio of petroleum ether:ethyl acetate = 5%:95%–25%:75%. After purification by vacuum concentration, approximately 0.2 g of the yellow solid product compound 3-e was obtained. MS m / z (ESI): 653.1 [M⁻¹] -

[0291] Step 5: Synthesis of Compound 3

[0292] 3-e (0.17 g, 0.25 mmol) was added to a reaction flask, dissolved in dichloroethane (2.5 mL), followed by the addition of trifluoromethanesulfonic acid (0.045 mL, 0.5 mmol). The mixture was heated to 80 °C and stirred for 2 hours. The residue was then concentrated and passed through a C1 filter. 18 Column purification was performed using an eluent ratio of 70% (acetonitrile):30% (ultrapure water [0.005% / L formic acid]) to 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 0.045 g of a yellow solid product, compound 3. MS m / z (ESI): 373.1 [M⁻¹] -

[0293] 1 H NMR(400MHz,DMSO)δ10.21(s,1H),7.89–7.80(m,1H),7.56(s,2H),7.44–7.36( m,2H),7.10(d,J=1.2Hz,1H),3.42(s,3H),2.40(d,J=1.2Hz,3H),2.01(s,3H).

[0294] Example 4: Preparation of Compound 4

[0295]

[0296] Step 1: Synthesis of compound 4-c

[0297] 1-b (420 mg, 2.51 mmol) was added to a two-necked flask and dissolved in tetrahydrofuran (3 mL). Then, 4-b (341.6 mL, 2.51 mmol) was added at room temperature. Under nitrogen protection, bis(trimethylsilylaminolithium) (6.3 mL, 6.3 mmol) was added dropwise at 25 °C. After the addition was complete, the reaction mixture was reacted at 25 °C for 1.5 h. The reaction solution was then poured into ice water (20 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a small amount of ethyl acetate was added to the resulting solid. The mixture was then filtered, and the residue was washed with a small amount of ethyl acetate to give 325 mg of a white solid, 4-c. MS m / z (ESI): 256.1 [M-1] -

[0298] Step 2: Synthesis of compound 4-e

[0299] 4-C (253 mg, 0.98 mmol) was added to a reaction flask, followed by dichloromethane (6 mL). Then, 2-E (800.4 mg, 3.93 mmol) and aluminum trichloride (393.2 mg, 2.9 mmol) were added under an ice-water bath. The reaction was carried out at room temperature for 2 hours under nitrogen protection. The mixture was cooled in an ice-water bath, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, slurried with ethyl acetate (2 mL), filtered, and the filter cake was dried to give 187 mg of a white solid, 4-E. MS m / z (ESI): 423.1 [M⁻¹] -

[0300] Step 3: Synthesis of compound 4-f

[0301] 4-e (200 mg, 0.47 mmol), N-fluorobis(benzenesulfonamide) (445.8 mg, 1.41 mmol), and 2,2,6,6-tetramethylpiperidine oxide (37.1 mg, 0.24 mmol) were dissolved in ethyl acetate (5 mL). The reaction was stopped after 18 h at 50 °C. The reaction solution was concentrated, and the residue was purified by C18 column chromatography at a ratio of 50% (acetonitrile):50% (ultrapure water [0.005% / L NH4HCO3]) to 62% (acetonitrile):38% (ultrapure water [0.005% / L NH4HCO3]). The purified product was collected and concentrated under reduced pressure to give approximately 175 mg of the yellow solid product compound 4-f. MS m / z (ESI): 718.1 [M-1]

[0302] Step 4: Synthesis of Compound 4

[0303] 4-F (175 mg, 0.24 mmol) was dissolved in dichloroethane (4 mL), followed by the addition of trifluoromethanesulfonic acid (0.13 mL, 0.2 mmol). The reaction was stopped after heating to 80 °C for 1 h. The reaction solution was concentrated, and the residue was purified by C18 column chromatography using an eluent ratio of 30% (acetonitrile):70% (ultrapure water [0.005% / L formic acid]) - 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give 20 mg of the yellow solid product compound 4. MS m / z (ESI): 438.1 [M-1]

[0304] 1H NMR (600MHz, DMSO) δ10.30 (s, 1H), 9.22 (d, J = 8.4Hz, 1H), 8.18-8.16 (m, 1H), 7.96-7.93 (m, 1H), 7.51 (t, J =9.6Hz,1H),7.33(s,1H),7.32(s,1H)4.71-4.67(m,1H),3.40(s,3H),2.12(s,3H),1.29(d,J=7.2Hz,3H).

[0305] Example 6 Preparation of Compound 6

[0306]

[0307] Step 1: Synthesis of compound 6-b

[0308] The procedure was the same as for the synthesis of compound 1-b, except that iodomethane was replaced with iodoethane (1.02 g, 6.53 mmol), yielding the crude, colorless, oily compound 6-b (1.7 g, 9.4 mmol). MS m / z (ESI): 182.1 [M+H] + .

[0309] Step 2: Synthesis of compound 6-c

[0310] The procedure was the same as for the synthesis of compound 1-d, except that 1-b was replaced with 6-b (800 mg, 4.42 mmol). After the reaction was basically complete as monitored by LCMS, water was added to quench the reaction, ethyl acetate (20 mL) was added to extract the aqueous phase, the organic phase was separated, dried over Na2SO4, filtered, concentrated, and then subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a grayish-white solid compound 6-c (580 mg, 2.2 mmol). MS m / z (ESI): 265.1 [M+H] + .

[0311] Step 3: Synthesis of compound 6-d

[0312] The procedure was the same as for the synthesis of compound 2-f, except that 1-d was replaced with 6-c (100 mg, 0.38 mmol), yielding a yellow solid compound 6-d (190 mg, 0.4 mmol). MS m / z (ESI): 432.2 [M+H] + .

[0313] Step 4: Synthesis of compound 6-e

[0314] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 6-d (160 mg, 0.37 mmol), yielding the yellow solid compound 6-e (50 mg, 0.07 mmol). MS m / z (ESI): 727.2 [M+H] + .

[0315] Step 5: Synthesis of Compound 6

[0316] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 6-e (50 mg, 0.07 mmol), yielding a yellow solid, compound 6 (13 mg). MS m / z (ESI): 447.1 [M+H] + .

[0317] 1 H NMR(600MHz, DMSO-d6)δ:10.24(s,1H),9.19(d,J=8.8Hz,1H),7.83(ddd,J=13.3,7.4,2.2Hz,1H),7.51–7.24( m, 4H), 4.68 (h, J = 7.6Hz, 1H), 3.95 (q, J = 7.1Hz, 2H), 2.10 (s, 3H), 1.29 (d, J = 7.0Hz, 3H), 1.13 (t, J = 7.0Hz, 3H).

[0318] Example 7 Preparation of Compound 7

[0319]

[0320] Step 1: Synthesis of compound 7-b

[0321] The procedure was the same as for the synthesis of compound 1-d, except that 3,4-difluoroaniline was replaced with 3,4,5-trifluoroaniline (492.7 mg, 3.35 mmol). After the starting material was consumed as monitored by LCMS, the reaction was quenched with water, extracted with ethyl acetate (20 mL), concentrated, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid compound 7-b (660 mg, 2.5 mmol). MS m / z (ESI): 269.1 [M+H] + .

[0322] Step 2: Synthesis of compound 7-c

[0323] The procedure was the same as for the synthesis of compound 2-f, except that 1-d was replaced with 7-b (100 mg, 0.37 mmol), yielding a yellow solid compound 7-c (260 mg, 0.6 mmol). MS m / z (ESI): 436.1 [M+H] + .

[0324] Step 3: Synthesis of compound 7-d

[0325] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 7-c (260 mg, 0.6 mmol), yielding a yellow solid compound 7-d (90 mg, 0.1 mmol). MS m / z (ESI): 731.0 [M+H] + .

[0326] Step 4: Synthesis of Compound 7

[0327] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 7-d (90 mg, 0.1 mmol), yielding a yellow solid compound 7 (10 mg). MS m / z (ESI): 451.1 [M+H] + .

[0328] 1 H NMR(600MHz,DMSO-d6)δ:10.28(s,1H),9.22(d,J=8.8Hz,1H),7.58(dd,J=10.4,6.4Hz,2 H),7.34(s,2H),4.69(h,J=7.6Hz,1H),3.39(s,3H),2.10(s,3H),1.29(d,J=7.1Hz,3H).

[0329] Example 8: Preparation of Compound 8

[0330]

[0331] Step 1: Synthesis of compound 8-a

[0332] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 3-a (1.66 g, 4.74 mmol), yielding the yellow solid compound 8-a (3.0 g, 4.75 mmol). MS m / z (ESI): 646.1 [M+H] + .

[0333] Step 2: Synthesis of compound 8-b

[0334] 8-a (1.60 g, 2.48 mmol) was added to a reaction flask and dissolved in 1,2-dichloroethane (30 mL). Trifluoromethanesulfonic acid (3.94 mL, 44.61 mmol) was then added. The mixture was heated to 80 °C and stirred for 1 hour. The solution was then concentrated to obtain a black oily compound, 8-b, which was used directly in the next step. MS m / z (ESI): 366.1 [M+H] + .

[0335] Step 3: Synthesis of compound 8-c

[0336] The crude 8-b product was dissolved in a mixed solvent of ethanol (9 mL) and water (3 mL). Sodium hydroxide (0.3 g, 7.43 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for approximately 1 hour. After the starting material was consumed as monitored by LC-MS, the pH was adjusted to approximately 5, and the ethanol was removed by concentration under reduced pressure. The residue was purified by C18 column chromatography using an eluent ratio of 70% (acetonitrile):30% (ultrapure water [0.005% / L formic acid]) - 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to obtain an orange-yellow solid compound 8-c (380 mg, 2.5 mmol). MS m / z (ESI): 338.1 [M+H] + .

[0337] Step 4: Synthesis of Compound 8

[0338] 8-c (60 mg, 0.18 mmol) and 8-d (24.4 mg, 0.22 mmol) were added to a reaction flask, dissolved in N,N-dimethylformamide (2 mL), and then N,N-diisopropylethylamine (46.5 mg, 0.36 mmol) was added. The mixture was stirred in an ice-water bath for one minute, and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (82.1 mg, 0.22 mmol) was added. The mixture was reacted in an ice-water bath for half an hour. The reaction solution was directly purified by a C18 column with an eluent ratio of 70% (acetonitrile):30% (ultrapure water [0.005% / L formic acid]) to 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to obtain an orange-yellow solid compound 8 (30 mg, 0.07 mmol). MS m / z(ESI): 432.12 [M+H] + .

[0339] 1H NMR (600MHz, DMSO) δ10.19 (s, 1H), 9.21 (d, J = 8.8Hz, 1H), 7.91-7.72 (m, 1H), 7.43-7.39 (m, 2H ),7.32(s,2H),4.69(m,J=15.5,7.7Hz,1H),3.39(s,3H),2.11(s,3H),1.29(d,J=7.0Hz,3H).

[0340] Example 9: Preparation of Compound 9

[0341]

[0342] Step 1: Synthesis of compound 9-a

[0343] 4-c (4.6 g, 17.88 mmol) was added to a reaction flask, followed by dichloromethane (100 mL). 2-b (10 mL, 89.39 mmol) and aluminum trichloride (16.7 g, 125.15 mmol) were added under an ice-water bath. The reaction was carried out at room temperature for approximately 2 hours under nitrogen protection. The reaction mixture was then quenched by slow dropwise addition of ice water (100 mL). The mixture was extracted with dichloromethane (200 mL), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid compound 9-a (4 g, 11.2 mmol). MS m / z (ESI): 358.11 [M+H] + .

[0344] Step 2: Synthesis of compound 9-b

[0345] 9-a (1.3 g, 3.64 mmol) and N-fluorobis(benzenesulfonamide) (22.9 g, 72.77 mmol) were added to a reaction flask, followed by ethyl acetate (50 mL) and then 2,2,6,6-tetramethylpiperidine oxide (5.7 g, 36.38 mmol). The reaction was carried out under nitrogen protection at 50 °C for 18 hours. The mixture was then concentrated and purified by a C18 column using an eluent ratio of 60% (acetonitrile):40% (ultrapure water [0.005% / L formic acid]) to 80% (acetonitrile):20% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give an orange-yellow solid compound 9-b (2.4 g, 3.64 mmol). MS m / z (ESI): 653.0 [M+H] + .

[0346] Step 3: Synthesis of compound 9-c

[0347] 9-b (2.4 g, 3.64 mmol) was added to a reaction flask and dissolved in 1,2-dichloroethane (20 mL). Trifluoromethanesulfonic acid (1.62 mL, 18.39 mmol) was then added. The mixture was heated to 80 °C and stirred for 20 minutes. The solvent was then evaporated to obtain a black, oily crude product, compound 9-c, which was used directly in the next step. MS m / z (ESI): 373.09 [M+H] + .

[0348] Step 4: Synthesis of compound 9-d

[0349] The procedure was the same as for the synthesis of compound 8-c, except that 8-b was replaced with 9-c, yielding an orange-yellow solid compound 9-d (750 mg, 2.18 mmol). MS m / z (ESI): 345.05 [M+H] + .

[0350] Step 4: Synthesis of Compound 9

[0351] The procedure was the same as for the synthesis of compound 8, except that 8-c was replaced with 9-d (30 mg, 0.09 mmol) and 8-d was replaced with 9-e (12.8 mg, 0.13 mmol), yielding a yellow solid, compound 9 (5.5 mg, 0.01 mmol). MS m / z (ESI): 422.17 [M+H] + .

[0352] 1 H NMR (600MHz, DMSO) δ10.26(s,1H),9.06(s,1H),8.17(dt,J=5.3,2.5Hz,1H),7.95(m,1H),7.51(t,J=9.1Hz,1H),7 .28(d,J=10.1Hz,1H),3.40(s,3H),3.28(d,J=1.4Hz,1H),2.38(t,J=7.7Hz,4H),2.20(s,3H),2.01–1.89(m,2H).

[0353] Example 10: Preparation of Compound 10

[0354]

[0355] Step 1: Synthesis of compound 10-b

[0356] The procedure was the same as for the synthesis of compound 1-b, except that iodomethane was replaced with deuterated iodomethane (0.5 g, 3.26 mmol), yielding the crude, colorless, oily compound 10-b (400 mg, 2.35 mmol). MS m / z (ESI): 171.1 [M+H] + .

[0357] Step 2: Synthesis of compound 10-c

[0358] The procedure was the same as for the synthesis of compound 1-d, except that 1-b was replaced with 10-b (400 mg, 2.35 mmol). After the reaction was basically complete as monitored by LCMS, water was added to quench the reaction, ethyl acetate (20 mL) was added to extract the aqueous phase, the organic phase was separated, dried over Na2SO4, filtered, concentrated, and then subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a grayish-white solid compound 10-c (340 mg, 1.34 mmol). MS m / z (ESI): 254.2 [M+H] + .

[0359] Step 3: Synthesis of compound 10-d

[0360] The procedure was the same as for the synthesis of compound 2-f, except that 1-d was replaced with 10-c (100 mg, 0.39 mmol), yielding a yellow solid compound 10-d (114 mg, 0.27 mmol). MS m / z (ESI): 421.3 [M+H] + .

[0361] Step 4: Synthesis of compound 10-e

[0362] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 10-d (114 mg, 0.27 mmol), yielding the yellow solid compound 10-e (50 mg, 0.07 mmol). MS m / z (ESI): 716.5 [M+H] + .

[0363] Step 5: Synthesis of Compound 10

[0364] The procedure was the same as for compound 2, except that 2-g was replaced with 10-e (50 mg, 0.07 mmol), yielding a yellow solid, compound 10 (13 mg). MS m / z (ESI): 436.1 [M+H] + .

[0365] 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.21(d,J=8.8Hz,1H),7.89–7.74(m,1 H),7.45–7.26(m,4H),4.74–4.60(m,1H),2.10(s,3H),1.29(d,J=7.0Hz,3H).

[0366] Example 11 Preparation of Compound 11

[0367]

[0368] Step 1: Synthesis of compound 11-b

[0369] 7-b (900 mg, 3.37 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Then, 2-b (10.05 g, 7.75 mmol) and aluminum trichloride (1.3 g, 10.1 mmol) were added under ice-water bath conditions. After reacting at room temperature for approximately 1 hour, the reaction solution was quenched with water. The mixture was extracted with dichloromethane (3 x 30 mL), and the organic phases were combined. The mixture was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a yellow solid compound 11-b (1.67 g, 4.53 mmol). MS m / z (ESI): 369.1 [M+H] + .

[0370] Step 2: Synthesis of compound 11-c

[0371] 11-b (1.67 g, 4.53 mmol) was added to a reaction flask, followed by EtOH (30 mL). A NaOH (2.2 g, 54.30 mmol) H₂O solution (15 mL) was added under ice-water bath conditions. The reaction was allowed to proceed at room temperature for 2 h. LC-MS was used to monitor the reaction completion. After impurities were extracted with ethyl acetate, the pH of the aqueous phase was adjusted to approximately 5 with dilute hydrochloric acid. Ethyl acetate was then added for further extraction, and the mixture was concentrated to obtain a white solid compound 11-c (870 mg, 2.56 mmol). MS m / z (ESI): 339.4 [MH] - .

[0372] Step 3: Synthesis of compound 11-d

[0373] 11-c (500 mg, 1.47 mmol), 8-d (166 mg, 1.47 mmol), DIEA (0.73 mL, 4.41 mmol), and solvent N,N-dimethylformamide (5 mL) were added to a reaction flask. HATU (670.3 mg, 1.76 mmol) was added in an ice-water bath, and the mixture was slowly heated to room temperature for 1 h. After the reaction was complete as monitored by LC-MS, water was added, and a solid precipitated. The solid obtained after filtration was the product, and after drying, a yellow solid compound 11-d (510 mg, 1.17 mmol) was obtained. MS m / z (ESI): 436.1 [M+H] + .

[0374] Step 4: Synthesis of compound 11-f

[0375] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 11-d (510 mg, 1.17 mmol), yielding a yellow solid compound 11-f (610 mg, 0.83 mmol). MS m / z (ESI): 731.2 [M+H] + .

[0376] Step 5: Synthesis of Compound 11

[0377] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 11-f (610 mg, 0.83 mmol), yielding a yellow solid, compound 11 (187 mg, 0.4 mmol). MS m / z (ESI): 451.1 [M+H] + .

[0378] 1 H NMR (600MHz, DMSO-d6) δ10.29(s,1H),9.22(d,J=8.8Hz,1H),7.59(dd,J=10.4,6.4 Hz,2H),7.34(s,2H),4.69(m,1H),3.39(s,3H),2.10(s,3H),1.29(d,J=7.0Hz,3H).

[0379] Example 12 Preparation of Compound 12

[0380]

[0381] Step 1: Synthesis of Compound 12

[0382] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 12-a (11 mg, 0.10 mmol), yielding an orange-yellow solid, compound 12 (15 mg, 0.04 mmol). MS m / z (ESI): 401.12 [M+H] + .

[0383] 1 H NMR (400MHz, DMSO) δ10.16(s,1H),9.14(s,1H),7.86–7.80(m,1H),7.42–7.37(m,2H),7.27(s,1H), 7.26(s,1H),3.38(s,3H),3.03(d,J=0.6Hz,1H),2.12(s,3H),1.16–1.13(m,2H),1.02–0.98(m,2H).

[0384] Example 13 Preparation of Compound 13

[0385]

[0386] Step 1: Synthesis of Compound 13

[0387] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 13-a (13.6 mg, 0.15 mmol), yielding a yellow solid, compound 13 (15 mg, 0.04 mmol). MS m / z (ESI): 383.31 [M+H] + .

[0388] 1 H NMR (600MHz, DMSO) δ10.31(s,1H),9.34(t,J=5.7Hz,1H),8.17(dd,J=5.8,2.7Hz,1H),7.94(ddd,J=9.2 ,4.9,2.7Hz,1H),7.51(t,J=9.1Hz,1H),7.36(s,2H),4.28(d,J=5.7Hz,2H),3.39(s,3H),2.12(s,3H).

[0389] Example 14 Preparation of Compound 14

[0390]

[0391] Step 1: Synthesis of Compound 14

[0392] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 12-a (12 mg, 0.15 mmol), yielding a yellow solid, compound 14 (15 mg, 0.04 mmol). MS m / z (ESI): 408.16 [M+H] + .

[0393] 1 H NMR (600MHz, DMSO) δ10.28(s,1H),9.14(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.94(ddd,J=9.2,4.9,2.7Hz,1H),7 .51(t,J=9.1Hz,1H),7.29(s,2H),3.39(s,3H),3.03(s,1H),2.13(s,3H),1.16–1.14(m,2H),1.02–0.99(m,2H).

[0394] Example 15 Preparation of Compound 15

[0395]

[0396] Step 1: Synthesis of Compound 15

[0397] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 8-d (0.29 mmol), yielding a yellow solid, compound 15 (30 mg, 0.06 mmol). MS m / z (ESI): 440.07 [M+H] + .

[0398] 1 H NMR (600MHz, DMSO) δ10.30(s,1H),9.21(d,J=8.8Hz,1H),8.17(dt,J=5.2,2.5Hz,1H),7.96–7.93(m,1H),7.51( t,J=9.1Hz,1H),7.33(s,1H),7.32(s,1H),4.72–4.66(m,1H),3.40(s,3H),2.12(s,3H),1.29(d,J=7.1Hz,3H).

[0399] Example 16 Preparation of Compound 16

[0400]

[0401] Step 1: Synthesis of compound 16-b

[0402] 16-a (4 g, 26.10 mmol) was added to a two-necked flask, dissolved in N,N-dimethylformamide (30 mL), and cooled to 0 °C. Under nitrogen protection, sodium hydride (2 g, 52.2 mmol) was added, and the mixture was stirred in an ice-water bath for 40 minutes. Iodimethane (1.95 mL, 31.14 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was slowly poured into ice water (100 mL), stirred for 2 minutes, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4.5 g of a pale yellow, transparent, oily product, compound 16-b. MS m / z (ESI): 173.60 [M+H] + .

[0403] Step 2: Synthesis of compound 16-c

[0404] 16-b (2.1 g, 12.10 mmol) was added to a two-necked flask and dissolved in tetrahydrofuran (30 mL). Then, 1-c (2.3 g, 18.15 mmol) was added at room temperature. Under nitrogen protection, bis(trimethylsilylaminolithium) (23.04 mL) was added dropwise at 25 °C. After the addition was complete, the mixture was reacted at 25 °C for approximately 1.5 hours. The reaction solution was then poured into ice water (20 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a small amount of ethyl acetate was added to the resulting solid. The mixture was then filtered, and the residue was washed with a small amount of ethyl acetate to give 2.7 g of a white solid, compound 16-c. MS m / z (ESI): 270.66 [M+H] + .

[0405] Step 3: Synthesis of compound 16-d

[0406] 16-c (2 g, 7.39 mmol) was added to a reaction flask and dissolved in dichloromethane (30 mL). Then, 2-b (1.5 g, 11.08 mmol) and aluminum trichloride (2.9 g, 22.16 mmol) were added under ice-water bath conditions. After reacting at room temperature for approximately 1 hour, the reaction was quenched with water. The dichloromethane was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2.3 g of a white solid compound 16-d. MS m / z (ESI): 372.75 [M+H] + .

[0407] Step 4: Synthesis of compound 16-e

[0408] 16-d (2.3 g, 6.20 mmol) was added to a reaction flask and dissolved in ethanol (25 mL). A solution of sodium hydroxide (0.7 g, 18.61 mmol) in water (3 mL) was added at 0 °C. After reacting for approximately 2 hours at 0 °C, a large amount of solid was produced. The reaction was stopped, and the solid was filtered. The remaining solution was washed with ethyl acetate (2 x 40 mL), and the organic layer was separated. The pH of the aqueous phase was adjusted to approximately 2. The ethanol was concentrated, and the aqueous phase was extracted with ethyl acetate (3 x 40 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the products were combined. Further concentration under reduced pressure yielded 1.9 g of a pale red solid compound, 16-e. MS m / z (ESI): 341.02 [MH] - .

[0409] Step 5: Synthesis of compound 16-f

[0410] Under ice-water bath conditions, 16-e (500 mg, 1.46 mmol) was added to a reaction flask, dissolved in N,N-dimethylformamide (5 mL), followed by 2-a (214.7 mg, 1.90 mmol), N,N-diisopropylethylamine (941.7 mg, 7.30 mmol), and finally 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (721.2 mg, 1.90 mmol). The mixture was stirred for 30 min under ice-water bath conditions, the reaction was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. The eluent ratio was petroleum ether:ethyl acetate = 7%:93%–12%:88%. After purification by reduced pressure concentration, 0.45 g of the pale yellow compound 16-f was finally obtained. MS m / z(ESI): 439.77 [M+H] + .

[0411] Step 6: Synthesis of compound 16-g

[0412] 16-F (450 mg, 1.03 mmol), N-fluorobis(benzenesulfonamide) (NFSI) (6.48 g, 20.60 mmol), and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) (1.61 mg, 10.30 mmol) were added to a reaction flask, dissolved in ethyl acetate (20 mL), and reacted at 50 °C for 5 hours. After cooling to room temperature, the residue was concentrated and purified by silica gel column chromatography with an eluent ratio of petroleum ether:ethyl acetate = 5%:95%–25%:75%. The purified product was concentrated under reduced pressure to give approximately 550 mg of a yellow solid, 16-g. MS m / z (ESI): 731.05 [MH] - .

[0413] Step 7: Synthesis of Compound 16

[0414] 16-g (400mg, 0.55mmol) was added to a reaction flask, dissolved in dichloroethane (10mL), and then trifluoromethanesulfonic acid (1.49g, 9.90mmol) was added. The mixture was heated to 90℃ and stirred for 2 hours. The mixture was then concentrated, and the residue was purified by C18 column chromatography. The eluent ratio was 70% (acetonitrile):30% (ultrapure water [0.005% / L formic acid]) - 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 55mg of a yellow solid compound 16. MS m / z (ESI): 452.77 [M+H] + .

[0415] 1H NMR(600MHz,DMSO)δ10.34(s,1H),9.19(d,J=8.4Hz,1H),7.84–7.80(m,1H) ,7.43-7.39(m,4H),4.69-4.63(m,1H),3.44(s,3H),1.28(d,J=6.6Hz,3H).

[0416] Example 17 Preparation of Compound 17

[0417]

[0418] Step 1: Synthesis of compound 17-b

[0419] The procedure was the same as for the synthesis of compound 16-b, except that 16-a was replaced with 17-a (2 g, 9.80 mmol), ultimately yielding 2.0 g of a pale yellow, transparent, oily product, compound 17-b. MS m / z (ESI): 218.05 [M+H] + .

[0420] Step 2: Synthesis of compound 17-c

[0421] The procedure was the same as for the synthesis of compound 16-c, except that 16-b was replaced with 17-b (2 g, 9.17 mmol), ultimately yielding 2.5 g of a white solid, compound 17-c. MS m / z (ESI): 315.12 [M+H] + .

[0422] Step 3: Synthesis of compound 17-d

[0423] The procedure was the same as for the synthesis of compound 16-d, except that 16-c was replaced with 17-c (750 mg, 2.38 mmol), yielding 0.85 g of a brown solid, compound 17-d. MS m / z (ESI): 417.21 [M+H] + .

[0424] Step 4: Synthesis of compound 17-e

[0425] The procedure was the same as for the synthesis of compound 16-e, except that 16-d was replaced with 17-d (850 mg, 2.05 mmol), yielding 0.62 g of a pale red solid, compound 17-e. MS m / z (ESI): 384.97 [M⁻¹] - .

[0426] Step 5: Synthesis of compound 17-f

[0427] The procedure was the same as for the synthesis of compound 16-f, except that 16-e was replaced with 17-e (620 mg, 1.60 mmol), ultimately yielding 0.45 g of the pale yellow product compound 17-f. MS m / z (ESI): 484.22 [M+H] + .

[0428] Step 6: Synthesis of compound 17-g

[0429] The procedure was the same as for the synthesis of compound 16-g, except that 16-f was replaced with 17-f (0.45 g, 0.93 mmol), yielding approximately 550 mg of the yellow solid product, compound 17-g. MS m / z (ESI): 775.00 [M⁻¹] - .

[0430] Step 7: Synthesis of Compound 17

[0431] The procedure was the same as for the synthesis of compound 16, except that 16-g was replaced with 17-g (400 mg, 0.51 mmol), yielding approximately 60 mg of the yellow solid product, compound 17. MS m / z (ESI): 497.22 [M+H] + .

[0432] 1H NMR (600MHz, DMSO) δ10.42(s,1H),9.17(d,J=8.7Hz,1H),7.83(dd,J=12.8,7.4Hz, 1H),7.42(t,J=8.5Hz,4H),4.70–4.60(m,1H),3.43(s,3H),1.30(d,J=7.0Hz,3H).

[0433] Example 18 Preparation of Compound 18

[0434]

[0435] Step 1: Synthesis of Compound 18

[0436] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 18-a (7.1 mg, 0.07 mmol), yielding 12 mg of the pale yellow product compound 18. MS m / z (ESI): 425.46 [M+H] + .

[0437] 1H NMR(600MHz,DMSO)δ10.25(s,1H),8.45(d,J=7.9Hz,1H),8.19–8.13(m,1H),7.94(ddd,J=7.6,5.0,2.6Hz,1H), 7.51(t,J=9.1Hz,1H),7.26(d,J=10.6Hz,2H),3.39(s,3H),2.16(s,3H),1.84–1.45(m,6H),1.34–1.04(m,6H).

[0438] Example 19 Preparation of Compound 19

[0439]

[0440] Step 1: Synthesis of Compound 19

[0441] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 19-a (5.1 mg, 0.06 mmol), yielding 10 mg of the pale yellow product, compound 19. MS m / z (ESI): 411.44 [M+H] + .

[0442] 1H NMR (600MHz, DMSO) δ10.25(s,1H),8.52(d,J=7.3Hz,1H),8.16(dd,J=5.7,2.6Hz,1H),7.95–7.89(m,1H),7.51(t,J=9.1Hz,1H), 7.26(d,J=10.6Hz,2H),3.39(s,3H),2.15(s,3H),1.83(dd,J=12.0,6.0Hz,2H),1.64(dd,J=8.8,5.9Hz,2H),1.57–1.40(m,5H).

[0443] Example 20 Preparation of Compound 20

[0444]

[0445] Step 1: Synthesis of compound 20-a

[0446] The procedure was the same as for the synthesis of compound 16-g, except that 16-f was replaced with 11-b (1 g, 2.72 mmol), ultimately yielding 1.2 g of the pale yellow product compound 20-a. MS m / z (ESI): 662.10 [M+H] - .

[0447] Step 2: Synthesis of compound 20-b

[0448] The procedure was the same as for the synthesis of compound 16, except that 16-g was replaced with 20-a (1.2 g, 1.80 mmol), yielding 420 mg of the pale yellow solid product, compound 20-b. MS m / z (ESI): 384.10 [M+H] + .

[0449] Step 3: Synthesis of compound 20-c

[0450] The procedure was the same as for the synthesis of compound 16-e, except that 16-d was replaced with 20-b (420 mg, 1.09 mmol), ultimately yielding 390 mg of the yellow product compound 20-c. MS m / z (ESI): 354.08 [MH] + .

[0451] Step 3: Synthesis of Compound 20

[0452] The procedure was the same as for the synthesis of compound 16-f, except that 16-e was replaced with 20-c (50 mg, 0.14 mmol) and 2-a was replaced with 20-d (34.8 mg, 0.21 mmol), yielding 25 mg of orange-yellow solid compound 20. MS m / z (ESI): 501.12 [M+H] + .

[0453] 1H NMR (400MHz, DMSO) δ10.32(s,1H),9.50(s,1H),7.81–7.51(m,3H),7.37(d,J=6.3Hz,2H),3.3 8(s,3H),3.28–3.17(m,2H),2.89(td,J=14.5,7.8Hz,2H),2.61(d,J=4.5Hz,3H),2.13(s,3H)

[0454] Example 21 Preparation of Compound 21

[0455]

[0456] Step 1: Synthesis of compound 21-a

[0457] The procedure was the same as for the synthesis of compound 16-c, except that 1-c was replaced with 4-b (2.4 g, 18.20 mmol), ultimately yielding 2.7 g of a white solid, compound 21-a. MS m / z (ESI): 270.66 [M+H] + .

[0458] Step 2: Synthesis of compound 21-b

[0459] The procedure was the same as for the synthesis of compound 16-d, except that 16-c was replaced with 21-a (2.7 g, 10.03 mmol), yielding 2.6 g of a brownish-white solid, compound 21-b. MS m / z (ESI): 379.77 [M+H] + .

[0460] Step 3: Synthesis of compound 21-c

[0461] The procedure was the same as for the synthesis of compound 16-e, except that 16-d was replaced with 21-b (2.6 g, 6.86 mmol), yielding 1.9 g of a pale red solid, compound 21-c. MS m / z (ESI): 348.02 [MH] - .

[0462] Step 5: Synthesis of compound 21-d

[0463] The procedure was the same as for the synthesis of compound 16-f, except that 16-e was replaced with 21-c (0.5 g, 1.43 mmol), ultimately yielding 0.45 g of the yellow product compound 21-d. MS m / z (ESI): 446.77 [M+H] + .

[0464] Step 6: Synthesis of compound 21-e

[0465] The procedure was the same as for the synthesis of compound 16-g, except that 16-f was replaced with 21-d (0.45 g, 1.12 mmol), yielding approximately 0.55 g of the yellow solid product, compound 21-e. MS m / z (ESI): 740.05 [MH] - .

[0466] Step 7: Synthesis of Compound 21

[0467] The procedure was the same as for the synthesis of compound 16, except that 16-g was replaced with 21-e (0.55 g, 0.74 mmol), yielding approximately 55 mg of the yellow solid product, compound 21. MS m / z (ESI): 459.79 [M+H] + .

[0468] 1H NMR (600MHz, DMSO) δ10.47(s,1H),9.20(d,J=9.0Hz,1H),8.17(dd,J=5.4,2.4Hz,1H),7.97-7.94( m,1H),7.53(t,J=10.2Hz,1H),7.45(s,2H),4.68-4.64(m,1H),3.45(s,3H),1.28(d,J=7.2Hz,3H).

[0469] Example 22 Preparation of Compound 22

[0470]

[0471] Step 1: Synthesis of compound 22-c

[0472] The procedure was the same as for the synthesis of compound 2-c, except that 2-a was replaced with 22-a (1 g, 11.47 mmol), yielding compound 22-c (2.3 g, 12.3 mmol). MS m / z (ESI): 188.14 [M+H] + .

[0473] Step 2: Synthesis of compound 22-d

[0474] The procedure was the same as for the synthesis of compound 2-d, except that 2-c was replaced with 22-c (2.3 g, 12.3 mmol), yielding compound 22-d (2 g, 12.56 mmol). MS m / z (ESI): 160.12 [M+H] + .

[0475] Step 3: Synthesis of compound 22-e

[0476] The procedure is the same as that for the synthesis of compound 2-e, except that 2-d is replaced with 22-d (150 mg, 0.94 mmol) to obtain compound 22-e, which is then used as a crude product.

[0477] Step 4: Synthesis of compound 22-f

[0478] The procedure was the same as for the synthesis of compound 2-f, except that 2-e was replaced with 22-e (167.3 mg, 0.94 mmol), yielding compound 22-f (160 mg, 0.4 mmol). MS m / z (ESI): 392.15 [M+H] + .

[0479] Step 5: Synthesis of compound 22-g

[0480] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 22-f (160 mg, 0.4 mmol), yielding compound 22-g (90 mg, 0.1 mmol). MS m / z (ESI): 687.16 [M+H] + .

[0481] Step 6: Synthesis of Compound 22

[0482] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 22-g (90 mg, 0.1 mmol), yielding compound 22 (6.8 mg, 0.02 mmol). MS m / z (ESI): 407.14 [M+H] + .

[0483] 1 H NMR(400MHz, DMSO-d6)δ10.14(s,1H),8.46(t,J=6.2Hz,1H),7.89–7.75(m,1H),7.44–7 .33(m,2H),7.28(s,2H),3.38(s,3H),2.99(d,J=6.2Hz,2H),2.14(s,3H),0.89(s,9H).

[0484] Example 23 Preparation of Compound 23

[0485]

[0486] Step 1: Synthesis of compound 23-c

[0487] The procedure was the same as for the synthesis of compound 2-c, except that 2-a was replaced with 23-a (0.2 g, 1.98 mmol), yielding compound 23-c (400 mg, 1.99 mmol). MS m / z (ESI): 202.16 [M+H] + .

[0488] Step 2: Synthesis of compound 23-d

[0489] The procedure was the same as for the synthesis of compound 2-d, except that 2-c was replaced with 23-c (400 mg, 1.99 mmol), yielding compound 23-d (362 mg, 2.1 mmol). MS m / z (ESI): 174.12 [M+H] + .

[0490] Step 3: Synthesis of compound 23-e

[0491] The procedure is the same as that for the synthesis of compound 2-e, except that 2-d is replaced with 23-d (150 mg, 0.87 mmol) to obtain compound 23-e, which is then used as a crude product.

[0492] Step 4: Synthesis of compound 23-f

[0493] The procedure was the same as for the synthesis of compound 2-f, except that 2-e was replaced with 23-e (99.6 mg, 0.52 mmol), yielding compound 23-f (160 mg, 0.4 mmol). MS m / z (ESI): 406.14 [M+H] + .

[0494] Step 5: Synthesis of compound 23-g

[0495] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 23-f (160 mg, 0.4 mmol), yielding compound 23-g (64 mg, 0.1 mmol). MS m / z (ESI): 701.15 [M+H] + .

[0496] Step 6: Synthesis of Compound 23

[0497] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 23-g (64 mg, 0.1 mmol), yielding compound 23 (18 mg, 0.04 mmol). MS m / z (ESI): 421.15 [M+H] + .

[0498] 1 H NMR (600MHz, DMSO-d6) δ10.18(s,1H),8.26(d,J=9.4Hz,1H),7.83(ddd,J=13.3,7.5,2.3Hz,1H),7.44–7.32(m ,2H),7.28(s,2H),3.76(dq,J=9.2,6.8Hz,1H),3.39(s,3H),2.16(s,3H),1.02(d,J=6.8Hz,3H),0.89(s,9H).

[0499] Example 24 Preparation of Compound 24

[0500]

[0501] Step 1: Synthesis of compound 24-c

[0502] The procedure was the same as for the synthesis of compound 2-c, except that 2-a was replaced with 24-a (300 mg, 2.96 mmol), yielding compound 24-c (557 mg, 2.8 mmol). MS m / z (ESI): 202.14 [M+H] + .

[0503] Step 2: Synthesis of compound 24-d

[0504] The procedure was the same as for the synthesis of compound 2-d, except that 2-c was replaced with 24-c (557 mg, 2.8 mmol), yielding compound 24-d (400 mg, 2.3 mmol). MS m / z (ESI): 172.3 [MH] - .

[0505] Step 3: Synthesis of compound 24-e

[0506] The procedure is the same as that for the synthesis of compound 2-e, except that 2-d is replaced with 24-d (400 mg, 2.3 mmol) to obtain compound 24-e, which is then used as a crude product.

[0507] Step 4: Synthesis of compound 24-f

[0508] The procedure was the same as for the synthesis of compound 2-f, except that 2-e was replaced with 24-e (459.7 mg, 2.4 mmol), yielding compound 24-f (130 mg, 0.32 mmol). MS m / z (ESI): 406.21 [M+H] + .

[0509] Step 5: Synthesis of compound 24-g

[0510] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 24-f (130 mg, 0.32 mmol), yielding compound 24-g (90 mg, 0.13 mmol). MS m / z (ESI): 701.1 [M+H] + .

[0511] Step 6: Synthesis of Compound 24

[0512] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 24-g (90 mg, 0.13 mmol), yielding compound 24 (9.1 mg, 0.02 mmol). MS m / z (ESI): 421.19 [M+H] + .

[0513] 1 H NMR (600MHz, DMSO) δ10.13(s,1H),8.26(d,J=9.4Hz,1H),7.86–7.79(m,1H),7.43–7.35(m,2H),7.24(d,J =11.2Hz,2H),3.76(dd,J=9.4,6.9Hz,1H),3.38(s,3H),2.16(s,3H),1.02(d,J=6.9Hz,3H),0.89(s,9H).

[0514] Example 25 Preparation of Compound 25

[0515]

[0516] Step 1: Synthesis of compound 25-c

[0517] 25-a (400 mg, 3.14 mmol) was added to a reaction flask and dissolved in dichloromethane (8 mL). N,N-diisopropylethylamine (0.67 mL, 3.76 mmol) was then added under ice-water bath conditions, followed by dropwise addition of 2-b (0.38 mL, 3.45 mmol). After the addition was complete, the reaction was carried out at 25°C for approximately 2 hours. The reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 550 mg of the yellow, transparent, oily product compound 25-b. MS m / z (ESI): 226.12 [M-1] - .

[0518] Step 2: Synthesis of compound 25-c

[0519] 25-b (550 mg, 2.42 mmol) was added to a reaction flask and dissolved in ethanol (10 mL). A solution of sodium hydroxide (0.29 g, 7.2 mmol) in water (5 mL) was then added at 0 °C. The reaction was allowed to proceed for approximately 2 hours at 0 °C until completion. After filtration, the filter cake was washed with ethanol to obtain a white solid. The pH of the filtrate was adjusted to approximately 2. The ethanol was concentrated, and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 350 mg of a white solid, compound 25-c. MS m / z (ESI): 198.14 [M⁻¹] -

[0520] Step 3: Synthesis of compound 25-d

[0521] Add 25-c (180 mg, 1.75 mmol) to the reaction flask, add 2 mL of thionyl chloride, heat under reflux for 1 hour, then stop the reaction and concentrate under reduced pressure to obtain 25-d for later use.

[0522] Step 4: Synthesis of compound 25-e

[0523] 1-d (0.2 g, 0.8 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Then, 25-d (0.3 g, 1.3 mmol) and aluminum trichloride (0.33 g, 2.5 mmol) were added under ice-water bath conditions. After reacting at room temperature for approximately 1 hour, the reaction solution was quenched with water. The dichloromethane was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 0.23 g of a yellow solid compound, 25-e. MS m / z (ESI): 432.21 [M+H] +

[0524] Step 5: Synthesis of compound 25-f

[0525] 25-e (0.23 g, 0.53 mmol), N-fluorobis(benzenesulfonamide) (0.84 g, 2.67 mmol), and 2,2,6,6-tetramethylpiperidine oxide (0.08 g, 0.53 mmol) were added to a reaction flask and dissolved in ethyl acetate (5 mL). The mixture was heated to 50 °C and reacted for 5 hours. The concentrate was then purified by C18 column chromatography at a ratio of 50% (acetonitrile):50% (ultrapure water [0.05% / L formic acid]) to 72% (acetonitrile):28% (ultrapure water [0.05% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 0.025 g of a yellow solid product, compound 25-f. MS m / z (ESI): 727.13 [M+H] +

[0526] Step 6: Synthesis of Compound 25

[0527] 25-F (0.025 g, 0.03 mmol) was added to a reaction flask, dissolved in 1,2-dichloroethane (2 mL), followed by the addition of trifluoromethanesulfonic acid (30 mg, 0.15 mmol). The mixture was heated to 80 °C and stirred for 2 hours. The residue was then concentrated and passed through a C1 filter. 18 Column purification was performed using an eluent ratio of 65% (acetonitrile):35% (ultrapure water [0.05% / L formic acid]) - 50% (acetonitrile):50% (ultrapure water [0.05% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 0.008 g of a yellow solid product, compound 25. MS m / z (ESI): 447.06 [M+H] +

[0528] 1 H NMR (600MHz, DMSO) δ10.16 (s, 1H), 8.67 (s, 1H), 7.83 (ddd, J = 13.4, 7.6, 2.1Hz ,1H),7.42–7.37(m,2H),7.26(s,2H),3.39(s,3H),2.15(s,3H),1.55(s,6H).

[0529] Example 26 Preparation of Compound 26

[0530]

[0531] Step 1: Synthesis of Compound 26

[0532] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 26-a (11 mg, 0.15 mmol), yielding a yellow solid, compound 26 (15 mg, 0.04 mmol). MS m / z (ESI): 393.15 [M+H] + .

[0533] 1 H NMR (400MHz, DMSO) δ10.12(s,1H),8.12(s,1H),7.86–7.80(m,1H),7.43–7. 36(m,2H),7.22(s,1H),7.20(s,1H),3.38(s,3H),2.19(s,3H),1.32(s,9H).

[0534] Example 27 Preparation of Compound 27

[0535]

[0536] Step 1: Synthesis of Compound 27

[0537] The procedure was the same as for compound 8, except that 8-d was replaced with 13-a (9 mg, 0.10 mmol), yielding a yellow solid, compound 27 (15 mg, 0.04 mmol). MS m / z (ESI): 376.13 [M+H] + .

[0538] 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 9.34 (t, J = 5.7Hz, 1H), 7.87–7.80 (m, 1H), 7.43–7. 37(m,2H),7.35(s,1H),7.34(s,1H),4.28(t,J=2.8Hz,2H),3.39(s,3H),2.10(s,3H).

[0539] Example 28 Preparation of Compound 28

[0540]

[0541] Step 1: Synthesis of Compound 28

[0542] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 3-c (8.3 mg, 0.15 mmol), yielding a yellow solid, compound 28 (15 mg, 0.04 mmol). MS m / z (ESI): 375.14 [M+H] + .

[0543] 1H NMR (600MHz, DMSO) δ10.17(s,1H),9.00(t,J=5.7Hz,1H),7.83(ddd,J=13.4,7.0,1.9Hz,1H),7.42–7. 37(m,2H),7.30(s,2H),3.96(dd,J=5.7,2.5Hz,2H),3.38(s,3H),3.14(t,J=2.5Hz,1H),2.12(s,3H).

[0544] Example 29 Preparation of Compound 29

[0545]

[0546] Step 1: Synthesis of Compound 29

[0547] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 29-a (8.3 mg, 0.10 mmol), yielding a yellow solid, compound 29 (15 mg, 0.04 mmol). MS m / z (ESI): 403.15 [M+H] + .

[0548] 1 H NMR (600MHz, DMSO) δ10.13(s,1H),8.62(s,1H),7.83(ddd,J=13.4,7.6,2.1Hz ,1H),7.42–7.36(m,2H),7.24(s,2H),3.38(s,3H),3.16(s,1H),1.54(s,6H).

[0549] Example 30 Preparation of Compound 30

[0550]

[0551] Step 1: Synthesis of Compound 30

[0552] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 30-a (12.5 mg, 0.15 mmol), yielding a yellow solid, compound 30 (9 mg, 0.02 mmol). MS m / z (ESI): 403.15 [M+H] + .

[0553] 1H NMR (600MHz, DMSO) δ10.13 (s, 1H), 9.05 (s, 1H), 7.83 (ddd, J = 13.3, 7.6, 2.1Hz, 1H), 7.42–7.38(m,2H),7.25(s,2H),3.38(s,3H),2.45(s,1H),2.13(s,3H),2.03(s,6H).

[0554] Example 31 Preparation of compound 31

[0555]

[0556] Step 1: Synthesis of Compound 31

[0557] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 31-a (18.5 mg, 0.15 mmol), yielding a yellow solid, compound 31 (11 mg, 0.02 mmol). MS m / z (ESI): 445.21 [M+H] + .

[0558] 1 H NMR (600MHz, DMSO) δ10.18(s,1H),9.36(s,1H),7.85–7.80(m,1H),7.43–7.36( m,2H),7.30(s,2H),3.38(s,3H),2.08(s,3H),1.34–1.29(m,2H),1.06(s,2H).

[0559] Example 32 Preparation of compound 32

[0560]

[0561] Step 1: Synthesis of Compound 32

[0562] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 32-a (13.7 mg, 0.15 mmol), yielding a yellow solid, compound 32 (16 mg, 0.02 mmol). MS m / z (ESI): 411.19 [M+H] + .

[0563] 1H NMR (600MHz, DMSO) δ10.14(s,1H),8.30(s,1H),7.83(ddd,J=13.3,7.5,2.3Hz,1H),7.44–7.37 (m,2H),7.24(s,2H),4.51(d,J=47.5Hz,2H),3.38(s,3H),2.17(s,3H),1.30(d,J=2.0Hz,6H).

[0564] Example 33 Preparation of compound 33

[0565]

[0566] Step 1: Synthesis of Compound 33

[0567] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 26-a (9.6 mg, 0.15 mmol), yielding a yellow solid, compound 33 (14 mg, 0.03 mmol). MS m / z (ESI): 400.19 [M+H] + .

[0568] 1 H NMR (600MHz, DMSO) δ10.23(s,1H),8.17(dd,J=5.8,2.7Hz,1H),8.13(s,1H),7.95(ddd,J=9.2 ,4.9,2.7Hz,1H),7.51(t,J=9.1Hz,1H),7.23(s,2H),3.39(s,3H),2.20(s,3H),1.32(s,9H).

[0569] Example 34 Preparation of compound 34

[0570]

[0571] Step 1: Synthesis of Compound 34

[0572] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 3-c (8.2 mg, 0.15 mmol), yielding a yellow solid compound 34 (10 mg, 0.03 mmol). MS m / z (ESI): 382.12 [M+H] + .

[0573] 1H NMR (600MHz, DMSO) δ10.29(s,1H),9.01(t,J=5.7Hz,1H),8.17(dd,J=5.8,2.7Hz,1H),7.94(ddd,J=9.2,4.9,2.7Hz,1 H),7.51(t,J=9.1Hz,1H),7.31(s,2H),3.96(dd,J=5.7,2.5Hz,2H),3.39(s,3H),3.14(t,J=2.5Hz,1H),2.14(s,3H).

[0574] Example 35 Preparation of compound 35

[0575]

[0576] Step 1: Synthesis of Compound 35

[0577] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 29-a (8.2 mg, 0.1 mmol), yielding a yellow solid, compound 35 (12 mg, 0.03 mmol). MS m / z (ESI): 382.12 [M+H] + .

[0578] 1 H NMR (600MHz, DMSO) δ10.25(s,1H),8.64(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.95(ddd,J=9.2,4.9, 2.7Hz,1H),7.51(t,J=9.1Hz,1H),7.25(s,2H),3.39(s,3H),3.16(s,1H),2.19(s,3H),1.54(s,6H).

[0579] Example 36 Preparation of compound 36

[0580]

[0581] Step 1: Synthesis of Compound 36

[0582] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 30-a (12.3 mg, 0.15 mmol), yielding a yellow solid, compound 36 (8 mg, 0.02 mmol). MS m / z (ESI): 410.18 [M+H] + .

[0583] 1H NMR (600MHz, DMSO) δ10.25(s,1H),9.07(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.95(ddd,J=9.2,4.8,2.7Hz ,1H),7.51(t,J=9.1Hz,1H),7.26(d,J=10.0Hz,2H),3.38(s,3H),2.45(s,1H),2.15(s,3H),2.04(s,6H).

[0584] Example 37 Preparation of Compound 37

[0585]

[0586] Step 1: Synthesis of Compound 37

[0587] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 31-a (18.5 mg, 0.15 mmol), yielding a yellow solid compound 37 (11 mg, 0.02 mmol). MS m / z (ESI): 452.12 [M+H] + .

[0588] 1 H NMR (600MHz, DMSO) δ10.30(s,1H),9.37(s,1H),8.16(dd,J=5.8,2.7Hz,1H),7.94(ddd,J=9.2,4.9,2.7 Hz,1H),7.51(t,J=9.1Hz,1H),7.32(s,2H),3.39(s,3H),2.10(s,3H),1.34–1.30(m,2H),1.06(s,2H).

[0589] Example 38 Preparation of compound 38

[0590]

[0591] Step 1: Synthesis of Compound 38

[0592] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 32-a (13.7 mg, 0.15 mmol), yielding a yellow solid, compound 38 (13 mg, 0.03 mmol). MS m / z (ESI): 418.18 [M+H] + .

[0593] 1H NMR (600MHz, DMSO) δ10.25(s,1H),8.31(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.95(ddd,J=9.2,4.9,2.7Hz,1H) ,7.51(t,J=9.1Hz,1H),7.26(s,2H),4.51(d,J=47.5Hz,2H),3.39(s,3H),2.19(s,3H),1.30(d,J=1.9Hz,6H).

[0594] Example 39 Preparation of compound 39

[0595]

[0596] Step 1: Synthesis of Compound 39

[0597] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 24-a (13.2 mg, 0.13 mmol), yielding 4 mg of compound 39. MS m / z (ESI): 428.18 [M+H] + .

[0598] 1 H NMR (600MHz, DMSO-d6) δ10.25(s,1H),8.27(d,J=9.4Hz,1H),8.17(dt,J=5.4,2.5Hz,1H),7.94(ddt,J=7.8,5.2,2.9Hz,1H),7.5 1(t,J=9.1Hz,1H),7.31–7.21(m,2H),3.77(dq,J=9.2,6.8Hz,1H),3.39(s,3H),2.17(s,3H),1.02(d,J=6.8Hz,3H),0.89(s,9H).

[0599] Example 40 Preparation of Compound 40

[0600]

[0601] Step 1: Synthesis of Compound 40

[0602] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 23-a (13.2 mg, 0.13 mmol), yielding 8 mg of compound 40. MS m / z (ESI): 428.38 [M+H] + .

[0603] 1H NMR (600MHz, DMSO-d6) δ10.25(s,1H),8.27(d,J=9.4Hz,1H),8.17(dt,J=5.6,2.5Hz,1H),7.94(ddt,J=8.0,5.1,2.9Hz,1H),7.51( t,J=9.1Hz,1H),7.26(d,J=10.9Hz,1H),3.77(dq,J=9.4,6.8Hz,1H),3.39(s,3H),2.17(s,3H),1.02(d,J=6.8Hz,3H),0.89(s,9H).

[0604] Example 41 Preparation of Compound 41

[0605]

[0606] Step 1: Synthesis of Compound 41

[0607] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 41-a (28 mg, 0.17 mmol), yielding a yellow solid, compound 41 (7.7 mg, 0.04 mmol). MS m / z (ESI): 454.12 [M+H] + .

[0608] 1 H NMR (600MHz, DMSO) δ10.28(s,1H),8.68(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.95(ddd,J=9. 2,4.9,2.7Hz,1H),7.51(t,J=9.1Hz,1H),7.28(s,2H),3.40(s,3H),2.17(s,3H),1.55(s,6H)

[0609] Example 42 Preparation of compound 42

[0610]

[0611] Step 1: Synthesis of Compound 42

[0612] Compound 105 (20 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (15.2 mg, 0.15 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added under ice-water bath conditions, and the mixture was stirred for 3 hours under ice-water bath conditions. The reaction was quenched with water. The solution was concentrated under reduced pressure to obtain a crude product, which was then purified to give 9.5 mg of a pale yellow solid, compound 42. MS m / z (ESI): 477.13 [M+H] + .

[0613] 1 HNMR (400MHz, DMSO) δ10.31 (s, 1H), 9.31 (d, J = 7.1Hz, 1H), 8.17 (dd, J = 5.8, 2.7Hz, 1H), 7.94 (m, 1H), 7.52 (t, J = 9.1Hz, 1H), 7.36(s,2H),4.59(dd,J=14.1,7.2Hz,1H),4.11(t,J=8.2Hz,2H),3.90–3.80(m,2H),3.39(s,3H),3.03(s,3H),2.12(s,3H).

[0614] Example 43 Preparation of compound 43

[0615]

[0616] Step 1: Synthesis of Compound 43

[0617] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 20-d (9.84 mg, 0.06 mmol), yielding 12 mg of the pale yellow product compound 43. MS m / z (ESI): 491.16 [M+H] + .

[0618] 1 H NMR (400MHz, DMSO) δ10.31(s,1H),9.43(s,1H),8.17(dd,J=5.7,2.6Hz,1H),7.94(ddd,J=9.0,4.8,2.7Hz,1H),7.59(d,J=4.6Hz,1H), 7.51(t,J=9.1Hz,1H),7.37(s,2H),3.39(s,3H),3.25–3.16(m,3H),2.90(dt,J=22.2,11.1Hz,2H),2.61(d,J=4.5Hz,3H),2.14(s,3H).

[0619] Example 44 Preparation of compound 44

[0620]

[0621] Step 1: Synthesis of Compound 44

[0622] The procedure was the same as for the synthesis of compound 20, except that 20-d was replaced with 44-a (23.6 mg, 0.17 mmol), yielding an orange-yellow solid compound 44 (25 mg). MS m / z (ESI): 479.11 [M+H] + .

[0623] 1H NMR (600MHz, DMSO) δ10.34(s,1H),9.76(s,1H),7.60(dd,J=10.3,6.4Hz,2H),7.40(s,2H),4.78(q,J=8.2Hz,4H),3.39(s,3H),2.16(s,3H)

[0624] Example 45 Preparation of Compound 45

[0625]

[0626] Step 1: Synthesis of compound 45-a

[0627] 17-g (500 mg, 0.60 mmol) and methyl fluorosulfonyl difluoroacetate (1383 mg, 7.2 mmol) were dissolved in NMP (50 mL), and cuprous iodide (381 mg, 2.0 mmol) was added to replace the N2 protection. The mixture was heated overnight at 80 °C until the reactants were consumed. After cooling to room temperature, the mixture was extracted twice with water (100 mL) and ethyl acetate (2 x 100 mL), washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was then purified by normal-phase medium-pressure preparative purification (PE / EA = 3 / 1) to give 45-a (150 mg, 0.20 mmol). MS m / z (ESI): 767.08 [M+H] + .

[0628] Step 2: Synthesis of Compound 45

[0629] The procedure was the same as for the synthesis of compound 16, except that 16-g was replaced with 45-a (150 mg, 0.20 mmol), yielding approximately 15 mg of the yellow solid product, compound 45. MS m / z (ESI): 487.10 [M+H] + .

[0630] 1 H NMR (400MHz, DMSO) δ11.06(s,1H),9.24(d,J=8.8Hz,1H),7.81(d,J=3.2Hz,1 H),7.58–7.28(m,4H),4.60(dt,J=54.0,23.1Hz,1H),1.28(d,J=7.0Hz,3H).

[0631] Example 46 Preparation of Compound 46

[0632]

[0633] Step 1: Synthesis of Compound 46

[0634] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 46-a (25 mg, 0.18 mmol), yielding a yellow solid, compound 46 (2.35 mg, 0.04 mmol). MS m / z (ESI): 464.15 [M+H] + .

[0635] 1 H NMR (600MHz, DMSO) δ10.29(s,1H),8.90(s,1H),8.17(dt,J=5.8,2.4Hz,1H),7.95(ddt,J=9.2,5.2,2.8Hz,1H),7.51(t,J= 9.1Hz,1H),7.30(d,J=10.1Hz,1H),5.20(t,J=5.7Hz,1H),3.56–3.53(m,2H),3.39(s,3H),2.87–2.76(m,4H),2.18(s,3H).

[0636] Example 47 Preparation of Compound 47

[0637]

[0638] Step 1: Synthesis of Compound 47

[0639] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 47-a (10 mg, 0.07 mmol), yielding a yellow solid, compound 47 (1.09 mg, 0.04 mmol). MS m / z (ESI): 462.11 [M+H] + .

[0640] 1 H NMR (600MHz, DMSO) δ10.28(s,1H),8.91(s,1H),8.17(dt,J=5.3,2.5Hz,1H),7.95(ddt,J=7.8,5.2,2.9Hz,1H),7.51(t,J=9.1Hz,1H),7. 30(d,J=10.1Hz,1H),3.40(s,3H),2.89–2.82(m,2H),2.68(q,J=12.9Hz,2H),2.18(s,3H),1.84(q,J=7.3Hz,2H),0.84(t,J=7.3Hz,3H).

[0641] Example 48 Preparation of Compound 48

[0642]

[0643] Step 1: Synthesis of compound 48-a

[0644] The procedure was the same as for the synthesis of compound 1-d, except that 1-b was replaced with 10-b (3 g, 17.63 mmol) and 1-c was replaced with 4-b. After the reaction was basically completed as monitored by LCMS, water was added to quench the reaction, ethyl acetate (20 mL) was added to extract the aqueous phase, the organic phase was separated, dried over Na2SO4, filtered, concentrated, and then slurried to obtain compound 48-a (3.2 g, 12.29 mmol). MS m / z (ESI): 261.14 [M+H] + .

[0645] Step 2: Synthesis of compound 48-b

[0646] The procedure was the same as for the synthesis of compound 11-b, except that 7-b was replaced with 48-a (2.2 g, 8.45 mmol). The reaction was carried out in an ice-water bath, monitored by LC-MS until completion, and quenched with water. The mixture was extracted with dichloromethane (3 x 30 mL), and the organic phases were combined. The mixture was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain compound 48-b (3 g, 8.32 mmol). MS m / z (ESI): 361.12 [M+H] + .

[0647] Step 3: Synthesis of compound 48-c

[0648] The procedure was the same as for the synthesis of compound 11-c, except that 11-b was replaced with 48-b (3 g, 8.32 mmol), yielding a yellow solid, compound 48-c (300 mg, 0.9 mmol). MS m / z (ESI): 333.09 [M+H] + .

[0649] Step 4: Synthesis of compound 48-d

[0650] The procedure was the same as for the synthesis of compound 11-d, except that 11-c was replaced with 48-c (300 mg, 0.9 mmol) and 8-d was replaced with 2-a, yielding compound 48-d (250 mg, 0.58 mmol). MS m / z (ESI): 428.11 [M+H] + .

[0651] Step 5: Synthesis of compound 48-e

[0652] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 48-d (250 mg, 0.58 mmol), yielding compound 48-e (310 mg, 0.43 mmol). MS m / z (ESI): 723.13 [M+H] + .

[0653] Step 6: Synthesis of Compound 48

[0654] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 48-e (310 mg, 0.43 mmol), yielding compound 48 (60 mg, 0.14 mmol). MS m / z (ESI): 443.11 [M+H] + .

[0655] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.24(d,J=8.8Hz,1H),8.18(dd,J=5.8,2.7Hz,1H),7.95(ddd,J=9.3,4 .9,2.7Hz,1H),7.53(t,J=9.1Hz,1H),7.35(s,2H),4.70(h,J=7.5Hz,1H),2.13(s,3H),1.30(d,J=7.0Hz,3H).

[0656] Example 49 Preparation of Compound 49

[0657]

[0658] Step 1: Synthesis of compound 49-b

[0659] The procedure was the same as for the synthesis of compound 1-d, except that 1-c was replaced with 49-a (870.8 mg, 5.98 mmol), yielding 512 mg of a yellow solid, compound 49-b. MS m / z (ESI): 267.07 [M+H] + .

[0660] Step 2: Synthesis of compound 49-c

[0661] The procedure was the same as for the synthesis of compound 2-f, except that 1-d was replaced with 49-b (500 mg, 1.87 mmol), yielding 355 mg of the yellow solid compound 49-c. MS m / z (ESI): 434.07 [M+H] + .

[0662] Step 3: Synthesis of compound 49-d

[0663] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 49-c (155 mg, 0.36 mmol), finally yielding 225 mg of the yellow compound 49-d. MS m / z (ESI): 729.15 [M+H] + .

[0664] Step 4: Synthesis of Compound 49

[0665] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 49-d (225 mg, 0.31 mmol), ultimately yielding 20 mg of the yellow product compound 49. MS m / z (ESI): 449.05 [M+H] + .

[0666] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.21(d,J=8.8Hz,1H),8.02–7.94(m,1H),7.62–7.55(m ,1H),7.44–7.30(m,3H),4.76–4.63(m,1H),3.39(s,3H),2.11(s,3H),1.29(d,J=7.0Hz,3H).

[0667] Example 50: Preparation of Compound 50

[0668]

[0669] Step 1: Synthesis of compound 50-a

[0670] The procedure was the same as for the synthesis of compound 9-b, except that 9-a was replaced with 21-b (0.6 g, 1.58 mmol), yielding 0.75 g of a brownish-yellow solid, compound 50-a. MS m / z (ESI): 673.31 [M+H] + .

[0671] Step 2: Synthesis of compound 50-b

[0672] The procedure was the same as for the synthesis of compound 9-c, except that 9-b was replaced with 50-a (0.6 g, 0.89 mmol), yielding a yellow solid compound 50-b (110 mg, 0.27 mmol). MS m / z (ESI): 393.13 [M+H] + .

[0673] Step 3: Synthesis of compound 50-c

[0674] The procedure was the same as for the synthesis of compound 9-d, except that 9-c was replaced with 50-b (110 mg, 0.27 mmol), yielding a yellow solid compound 50-c (80 mg, 0.21 mmol). MS m / z (ESI): 365.21 [M+H] + .

[0675] Step 4: Synthesis of Compound 50

[0676] The procedure was the same as for the synthesis of compound 8, except that 8-c was replaced with 50-c (70 mg, 0.19 mmol), yielding a yellow solid, compound 50 (13.2 mg, 0.02 mmol). MS m / z (ESI): 459.18 [M+H] + .

[0677] 1 H NMR (400MHz, DMSO) δ10.46(s,1H),9.20(d,J=8.7Hz,1H),8.17(ddd,J=5.7,2.7,1.4Hz,1H),7.96(ddt,J=9.3,4.9, 2.4Hz, 1H), 7.53 (t, J = 9.1Hz, 1H), 7.44 (d, J = 4.1Hz, 2H), 4.66 (q, J = 7.7Hz, 1H), 3.45 (s, 3H), 1.28 (d, J = 7.0Hz, 3H).

[0678] Example 51 Preparation of Compound 51

[0679]

[0680] Step 1: Synthesis of Compound 51

[0681] The procedure was the same as for the synthesis of compound 20, except that 20-d was replaced with 51-a (58.2 mg, 0.33 mmol), yielding an orange-yellow solid compound 51 (25 mg, 0.04 mmol). MS m / z (ESI): 512.15 [M+H] + .

[0682] 1 H NMR (600MHz, DMSO) δ10.27(s,1H),9.60(s,1H),7.76(s,1H),7.58(ddd,J=9.6,6.5,2.2 Hz,2H),7.33(d,J=9.6Hz,1H),3.38(s,3H),3.24(dd,J=24.5,12.8Hz,4H),2.02(s,3H).

[0683] Example 52 Preparation of Compound 52

[0684]

[0685] Step 1: Synthesis of compound 52-a

[0686] The procedure was the same as for the synthesis of compound 17-c, except that 1-c was replaced with 4-b (1 g, 4.58 mmol), ultimately yielding 950 mg of white solid compound 52-a. MS m / z (ESI): 321.99 [M+H] + .

[0687] Step 2: Synthesis of compound 52-b

[0688] The procedure was the same as for the synthesis of compound 17-d, except that 17-c was replaced with 52-a (950 mg, 2.95 mmol), yielding 0.85 g of a brown solid, compound 52-b. MS m / z (ESI): 422.01 [M+H] + .

[0689] Step 3: Synthesis of compound 52-c

[0690] The procedure was the same as for the synthesis of compound 17-e, except that 17-d was replaced with 52-b (850 mg, 2.05 mmol), yielding 0.57 g of a pale red solid, compound 52-c. MS m / z (ESI): 391.08 [M⁻¹] - .

[0691] Step 4: Synthesis of compound 52-d

[0692] The procedure was the same as for the synthesis of compound 17-f, except that 17-e was replaced with 52-c (570 mg, 1.46 mmol), ultimately yielding 0.45 g of the pale yellow product compound 52-d. MS m / z (ESI): 489.01 [M+H] + .

[0693] Step 5: Synthesis of compound 52-e

[0694] The procedure was the same as for the synthesis of compound 17-g, except that 17-f was replaced with 52-d (0.45 g, 0.92 mmol), yielding approximately 550 mg of the yellow solid product compound 52-e. MS m / z (ESI): 783.00 [M⁻¹] - .

[0695] Step 6: Synthesis of compound 52-f

[0696] The procedure was the same as for the synthesis of compound 45-a, except that 17-g was replaced with 52-e (550 mg, 0.71 mmol), yielding 80 mg of the yellow solid product, compound 52-f. MS m / z (ESI): 774.08 [M+H] +

[0697] Step 7: Synthesis of Compound 52

[0698] The procedure was the same as for the synthesis of compound 17, except that 17-g was replaced with 52-f (80 mg, 0.10 mmol), yielding approximately 8 mg of the yellow solid product, compound 52. MS m / z (ESI): 494.10 [M+H] + .

[0699] 1 H NMR (400MHz, DMSO) δ11.23(s,1H),9.25(d,J=8.8Hz,1H),8.16(dd,J=5.7,2.6Hz,1H),7.97–7.83(m,1H ),7.56(t,J=9.1Hz,1H),7.46(s,2H),4.64(dd,J=15.1,7.6Hz,1H),3.37(s,3H),1.28(d,J=7.0Hz,4H).

[0700] Example 53 Preparation of compound 53

[0701]

[0702] Step 1: Synthesis of 53-a

[0703] The procedure was the same as for the synthesis of compound 16-b, except that iodomethane was replaced with deuterated iodomethane (1.95 mL, 31.14 mmol), yielding 4.5 g of a pale yellow, transparent oily product, compound 53-a. MS m / z (ESI): 177.05 [M+H] + .

[0704] Step 2: Synthesis of compound 53-b

[0705] The procedure was the same as for the synthesis of compound 16-c, except that 16-b was replaced with 53-a (4.5 g, 25.42 mmol) and 1-c was replaced with 4-b (4.14 g, 30.49 mmol), yielding 5 g of pale yellow solid compound 53-b. MS m / z (ESI): 281.06 [M+H] + .

[0706] Step 3: Synthesis of compound 53-c

[0707] The procedure was the same as for the synthesis of compound 16-d, except that 16-c was replaced with 53-b (5 g, 17.79 mmol), yielding 3.5 g of a pale yellow solid, compound 53-c. MS m / z (ESI): 381.08 [M+H] + .

[0708] Step 4: Synthesis of compound 53-d

[0709] The procedure was the same as for the synthesis of compound 16-e, except that 16-d was replaced with 53-c (3.5 g, 9.18 mmol), yielding 3.1 g of a pale yellow solid, compound 53-d. MS m / z (ESI): 351.05 [M+H] - .

[0710] Step 5: Synthesis of compound 53-e

[0711] The procedure was the same as for the synthesis of compound 16-f, except that 16-e was replaced with 53-d (3.1 g, 8.83 mmol), yielding 3 g of a pale yellow solid, compound 53-e. MS m / z (ESI): 448.08 [M+H] + .

[0712] Step 6: Synthesis of compound 53-f

[0713] The procedure was the same as for the synthesis of compound 16-g, except that 16-f was replaced with 53-e (3 g, 6.69 mmol), yielding 3.1 g of a pale yellow solid, compound 53-f. MS m / z (ESI): 743.08 [M+H] + .

[0714] Step 7: Synthesis of Compound 53

[0715] The procedure was the same as for the synthesis of compound 16, except that 16-g was replaced with 53-f (3.1g, 4.17mmol), yielding 350mg of a pale yellow solid, compound 53. MS m / z (ESI): 463.09 [M+H] + .

[0716] 1 H NMR (600MHz, DMSO) δ10.46(s,1H),9.19(d,J=8.7Hz,1H),8.17(dd,J=5.7,2.6Hz,1H),7.95(ddd,J=8.9,4 .7,2.7Hz,1H),7.53(t,J=9.1Hz,1H),7.44(d,J=5.8Hz,2H),4.66(d,J=7.6Hz,1H),1.28(d,J=7.0Hz,3H).

[0717] Example 54 Preparation of Compound 54

[0718]

[0719] Step 1: Synthesis of Compound 54

[0720] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 54-a (8.5 mg, 0.07 mmol), yielding a yellow solid, compound 54 (5 mg, 0.01 mmol). MS m / z (ESI): 414.10 [M+H] + .

[0721] 1 H NMR (600MHz, DMSO) δ10.29(s,1H),9.08(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.97-7.93(m,1H),7.51(t,J=9 .1Hz,1H),7.32(s,2H),4.66(d,J=6.3Hz,2H),4.37(d,J=6.3Hz,2H),3.40(s,3H),2.20(s,3H),1.57(s,3H).

[0722] Example 55 Preparation of compound 55

[0723]

[0724] Step 1: Synthesis of Compound 55

[0725] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 55-a (8 mg, 0.07 mmol), yielding a yellow solid compound 55 (20 mg, 0.05 mmol). MS m / z (ESI): 442.48 [M+H] + .

[0726] 1 H NMR (600MHz, DMSO) δ10.24(s,1H),8.18-8.16(m,2H),7.97-7.94(m,1H),7.51(t,J=9.1Hz,1H),7.26(s ,2H),3.63–3.52(m,4H),3.40(s,3H),2.21(s,3H),2.12–2.06(m,2H),1.56-1.52(m,2H),1.37(s,3H).

[0727] Example 56 Preparation of Compound 56

[0728]

[0729] Step 1: Synthesis of Compound 56

[0730] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 56-a (7.2 mg, 0.07 mmol), yielding a yellow solid compound 56 (20 mg, 0.05 mmol). MS m / z (ESI): 430.17 [M+H] + .

[0731] 1 H NMR (600MHz, DMSO) δ10.25 (s, 1H), 8.17 (dd, J = 5.8, 2.7Hz, 1H), 8.05 (s, 1H), 7.97-7.93 (m, 1H), 7. 51(t,J=9.1Hz,1H),7.23(s,2H),3.43(s,2H),3.39(s,3H),3.26(s,3H),2.20(s,3H),1.28(s,6H).

[0732] Example 57 Preparation of Compound 57

[0733]

[0734] Step 1: Synthesis of Compound 57

[0735] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 57-a (16.2 mg, 0.1 mmol), yielding a yellow solid compound 57 (20 mg, 0.04 mmol). MS m / z (ESI): 462.14 [M+H] + .

[0736] 1 H NMR (600MHz, DMSO) δ10.27(s,1H),8.61(d,J=7.7Hz,1H),8.16(dd,J=5.8,2.7Hz,1H),7.96-7.92(m,1H),7.51(t,J=9.1H z,1H),7.29(s,2H),3.89-3.85(m,1H),3.39(s,3H),2.15(s,3H),2.06–1.90(m,4H),1.86-1.82m,2H),1.58–1.51(m,2H).

[0737] Example 58 Preparation of compound 58

[0738]

[0739] Step 1: Synthesis of Compound 58

[0740] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 58-a (8.4 mg, 0.12 mmol), yielding a yellow solid compound 58 (20 mg, 0.05 mmol). MS m / z (ESI): 444.12 [M+H] + .

[0741] 1 H NMR (600MHz, DMSO) δ10.27(s,1H),8.60(d,J=8.0Hz,1H),8.16(dd,J=5.8,2.7Hz,1H),7.96-7.92(m,1H),7.51(t,J=9.1Hz ,1H),7.28(s,2H),3.73-3.69(m,1H),3.39(s,3H),2.71–2.62(m,4H),2.15(s,3H),2.06-2.02(m,2H),1.59-1.55(m,2H).

[0742] Example 59 Preparation of Compound 59

[0743]

[0744] Step 1: Synthesis of Compound 59

[0745] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 59-a (17.3 mg, 0.15 mmol), yielding a yellow solid, compound 59 (18 mg, 0.04 mmol). MS m / z (ESI): 442.14 [M+H] + .

[0746] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.47(d,J=7.6Hz,1H),8.17(ddd,J=5.8,2 .7,1.4Hz,1H),7.95(dddd,J=9.4,4.8,2.8,2.0Hz,1H),7.51(t,J=9.2Hz,1H),7. 26(d,J=7.2Hz,2H),4.37(s,1H),3.68(dd,J=15.5,5.2Hz,2H),3.39(s,3H),2.16 (s,3H),1.64(td,J=13.6,12.9,4.0Hz,4H),1.48(ddd,J=16.7,10.1,3.7Hz,4H).

[0747] Example 60 Preparation of Compound 60

[0748]

[0749] Step 1: Synthesis of Compound 60

[0750] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 60-a (13.4 mg, 0.15 mmol), yielding a yellow solid, compound 60 (15 mg, 0.04 mmol). MS m / z (ESI): 416.23 [M+H] + .

[0751] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.31–8.25(m,1H),8.17(ddd,J=5.8,2.8,1.4Hz, 1H),8.02–7.85(m,1H),7.51(t,J=9.2Hz,1H),7.29(d,J=7.3Hz,2H),4.68(s,1H),3.70 (dt,J=8.4,5.9Hz,1H),3.43(dd,J=10.7,5.3Hz,2H),3.39(s,3H),2.18(s,3H),1.64(d qd,J=15.0,7.5,4.8Hz,1H),1.38(ddd,J=13.6,8.6,7.2Hz,1H),0.87(t,J=7.4Hz,3H).

[0752] Example 61 Preparation of Compound 61

[0753]

[0754] Step 1: Synthesis of Compound 61

[0755] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 61-a (18.5 mg, 0.15 mmol), yielding a yellow solid compound 61 (7 mg, 0.02 mmol). MS m / z (ESI): 414.12 [M+H] + .

[0756] 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.82(d,J=7.0Hz,1H),8.17(dd,J=5.8,2.7Hz,1H),7.94(ddd,J=9.3,4.9,2.7Hz,1H),7.51(t,J=9.1Hz,1H),7. 28(d,J=10.3Hz,2H),5.04(s,1H),4.27(p,J=4.9Hz,2H),3.39(s,3H),2.18 (dd,J=7.0,4.8Hz,2H),2.13(s,3H),2.12–2.09(m,1H),2.03–1.96(m,1H).

[0757] Example 62 Preparation of compound 62

[0758]

[0759] Step 1: Synthesis of Compound 62

[0760] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 62-a (24.8 mg, 0.15 mmol), yielding a yellow solid, compound 62 (19 mg, 0.04 mmol). MS m / z (ESI): 456.18 [M+H] + .

[0761] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.42(s,1H),8.19(ddd,J=5.8,2.7,1.3H z,1H),7.98(ddt,J=7.2,4.8,2.4Hz,2H),7.53(t,J=9.2Hz,1H),7.25(d,J=7.4 Hz,1H),3.64–3.55(m,1H),3.41(s,3H),2.23(s,3H),1.83(td,J=8.5,8.0,4.2 Hz,2H),1.79–1.74(m,2H),1.72–1.63(m,2H),1.44–1.37(m,2H),1.35(s,3H).

[0762] Example 63 Preparation of compound 63

[0763]

[0764] Step 1: Synthesis of Compound 63

[0765] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 63-a (20.6 mg, 0.15 mmol), yielding a yellow solid, compound 63 (20 mg, 0.04 mmol). MS m / z (ESI): 464.04 [M+H] + .

[0766] 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),10.31(s,1H),8.40(s,1H),8.19(dd,J=6.4,2.6Hz,1H),7.95(dt,J=9.7,2.5Hz,2H), 7.73(d,J=8.1Hz,1H),7.52(dd,J=10.9,8.0Hz,2H),7.37(d,J=6.4Hz,1H),7.31(t,J=7.7Hz,1H),3.44(s,3H),2.16(s,3H).

[0767] Example 64 Preparation of Compound 64

[0768]

[0769] Step 1: Synthesis of Compound 64

[0770] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 64-a (11.3 mg, 0.15 mmol), yielding a yellow solid, compound 64 (7 mg, 0.02 mmol). MS m / z (ESI): 402.13 [M+H] + .

[0771] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.35(d,J=8.0Hz,1H),8.19(ddd,J=5.9,2.8,1.5Hz,1H),7.96(ddt,J=9.4,4.9,2.3Hz,1H),7.53(t,J=9.1Hz, 1H),7.31(s,1H),7.29(s,1H),3.87(dt,J=13.8,6.7Hz,1H),3.50–3.43(m ,1H),3.41(s,3H),3.30–3.25(m,2H),2.19(s,3H),1.11(d,J=6.7Hz,3H).

[0772] Example 65 Preparation of compound 65

[0773]

[0774] Step 1: Synthesis of compound 65-a

[0775] The procedure was the same as for the synthesis of compound 1-b, except that 1-a was replaced with 17-a (3 g, 14.71 mmol) and iodomethane was replaced with deuterated iodomethane, yielding compound 65-a (2.3 g, 10.40 mmol). MS m / z (ESI): 223.15 [M+H] + .

[0776] Step 2: Synthesis of compound 65-b

[0777] The procedure was the same as for the synthesis of compound 1-d, except that 1-b was replaced with 65-a (2.3 g, 10.40 mmol) and 1-c was replaced with 4-b, yielding compound 65-b (1.6 g, 4.92 mmol). MS m / z (ESI): 326.99 [M+H] + .

[0778] Step 3: Synthesis of compound 65-c

[0779] The procedure was the same as for the synthesis of compound 11-b, except that 7-b was replaced with 65-b (1.6 g, 4.92 mmol), yielding compound 65-c (2 g, 4.70 mmol). MS m / z (ESI): 426.99 [M+H] + .

[0780] Step 4: Synthesis of compound 65-d

[0781] The procedure was the same as for the synthesis of compound 11-c, except that 11-b was replaced with 65-c (2 g, 4.70 mmol), yielding compound 65-d (1.8 g, 4.53 mmol). MS m / z (ESI): 396.2 [MH] - .

[0782] Step 5: Synthesis of compound 65-e

[0783] The procedure was the same as for the synthesis of compound 11-d, except that 11-c was replaced with 65-d (1.8 g, 4.53 mmol) and 8-d was replaced with 2-a, yielding compound 65-e (1.8 g, 3.66 mmol). MS m / z (ESI): 490.1 [M+H] + .

[0784] Step 6: Synthesis of compound 65-f

[0785] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 65-e (1.6 g, 3.25 mmol), yielding compound 65-f (1.9 g, 2.41 mmol). MS m / z (ESI): 787.7 [M+H] + .

[0786] Step 7: Synthesis of Compound 65

[0787] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 65-f (300 mg, 0.38 mmol) to obtain compound 65 (60 mg, 0.12 mmol). MS m / z (ESI): 509.08 [M+H] + .

[0788] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.20(d,J=8.7Hz,1H),8.31–8.13(m,1H),7.99(ddt,J=9.4,4. 7,2.2Hz,1H),7.56(t,J=9.1Hz,1H),7.46(d,J=5.0Hz,2H),4.78–4.55(m,1H),1.32(d,J=7.1Hz,3H).

[0789] Example 66 Preparation of Compound 66

[0790]

[0791] Step 1: Synthesis of compound 66-b

[0792] 66-a (1300 mg, 7.69 mmol) was dissolved in anhydrous DCM (13 mL). While cooling in an ice-water bath, 5 mL of DAST (5.08 mL, 38.44 mmol) DCM solution was slowly added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 1 hour, then overnight at room temperature. The reaction solution was then slowly added dropwise to ice water (50 mL), followed by extraction with DCM (50 mL). The organic layer was washed with saturated NaHCO3 (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.29 g of a colorless oily compound 66-b. 1 H NMR (400MHz, DMSO-d6) δ8.54–8.46(m,2H),7.77–7.67(m,1H),7.34(t,J=53.6Hz,1H).

[0793] Step 2: Synthesis of compound 66-c

[0794] Compound 66-b (1290 mg, 6.75 mmol) was dissolved in methanol (25 mL). Concentrated hydrochloric acid (6.77 mL, 81.00 mmol) was slowly added dropwise under ice-water bath cooling. After the addition was complete, reduced iron powder (1506.7 mg, 27.00 mmol) was added in portions, and the reaction was allowed to proceed at room temperature for 1.5 hours. The reaction mixture was added dropwise to a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (2 x 100 mL), and the organic layers were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 1.0 g of a brown oily product, 66-c. MS m / z (ESI): 162.08 [M+H] + .

[0795] Step 3: Synthesis of compound 66-d

[0796] The procedure was the same as for the synthesis of compound 1-d, except that 1-c was replaced with 66-c (1.0 g, 5.98 mmol), yielding 685 mg of a yellow solid, compound 66-d. MS m / z (ESI): 283.07 [M+H] + .

[0797] Step 4: Synthesis of compound 66-e

[0798] The procedure was the same as for the synthesis of compound 11-b, except that 7-b was replaced with 66-d (435 mg, 1.54 mmol), ultimately yielding 220 mg of the yellow solid compound 66-e. MS m / z (ESI): 383.11 [M+H] + .

[0799] Step 5: Synthesis of compound 66-f

[0800] 66-e (220 mg, 0.58 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (3 mL), and cooled to 0 °C. An aqueous solution (3 mL) containing lithium hydroxide monohydrate (72.5 mg, 1.73 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for half an hour. The volatile organic compounds were evaporated using a rotary evaporator. The pH of the reaction mixture was adjusted to approximately 5 with 1 M dilute hydrochloric acid, diluted with water (20 mL), and extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 137 mg of product 66-f. MS m / z (ESI): 355.09 [M+H] + .

[0801] Step 6: Synthesis of compound 66-g

[0802] The procedure was the same as for the synthesis of compound 11-d, except that 11-c was replaced with 66-f (500 mg, 1.87 mmol) and 8-d was replaced with 2-a (86.7 mg, 0.58 mmol), yielding 92 mg of a yellow solid, 66-g. MS m / z (ESI): 448.08 [MH] - .

[0803] Step 7: Synthesis of compound 66-h

[0804] The procedure was the same as for the synthesis of compound 11-f, except that 11-d was replaced with 66-g (92 mg, 0.20 mmol), yielding 200 mg of the yellow oily compound 66-h. MS m / z (ESI): 745.09 [M+H] + .

[0805] Step 8: Synthesis of Compound 66

[0806] The procedure was the same as for the synthesis of compound 11, except that 11-f was replaced with 66-h (200 mg, 0.27 mmol), ultimately yielding 10 mg of the yellow product compound 66. MS m / z (ESI): 465.14 [M+H] + .

[0807] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.22(d,J=8.8Hz,1H),8.09–8.02(m,1H),7.86–7.78(m ,1H),7.41–7.06(m,3H),4.77–4.64(m,1H),3.42(s,3H),2.14(s,3H),1.31(d,J=7.1Hz,3H).

[0808] Example 67 Preparation of Compound 67

[0809]

[0810] Step 1: Synthesis of compound 67-a

[0811] 65-F (300 mg, 0.38 mmol), methyl fluorosulfonyl difluoroacetate (0.73 mL, 5.71 mmol), and CuI (145.1 mg, 0.76 mmol) were dissolved in NMP (10 mL), reacted overnight at 80 °C under nitrogen protection, quenched with water, extracted with ethyl acetate (20 mL), and concentrated to C 18Column purification, eluent ratio: 70% (acetonitrile): 30% (ultrapure water [0.005% / L formic acid]) - 20% (acetonitrile): 80% (ultrapure water [0.005% / L formic acid]), yielded compound 67-a (80 mg, 0.10 mmol). MS m / z (ESI): 777.08 [M+H] + .

[0812] Step 2: Synthesis of Compound 67

[0813] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 67-a (80 mg, 0.10 mmol), yielding compound 67 (13 mg, 0.03 mmol). MS m / z (ESI): 497.23 [M+H] + .

[0814] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),9.27(d,J=8.9Hz,1H),8.19(dd,J=5.8,2.7Hz,1H),7.95(ddd,J=8. 7,5.1,2.8Hz,1H),7.59(t,J=9.1Hz,1H),7.47(d,J=6.7Hz,2H),4.77–4.51(m,1H),1.31(d,J=7.1Hz,3H).

[0815] Example 68 Preparation of Compound 68

[0816]

[0817] Step 1: Synthesis of Compound 68

[0818] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 68-a (14.7 mg, 0.11 mmol), yielding a yellow solid, compound 68 (12 mg, 0.03 mmol). MS m / z (ESI): 456.11 [M+H] + .

[0819] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.32(s,1H),8.21-8.16(m,1H),7.99-7.92(m,1H) ),7.88-7.80(m,1H),7.53(t,J=9.1Hz,1H),7.49-7.41(m,3H),3.44(s,3H),2.13(s,3H).

[0820] Example 69 Preparation of Compound 69

[0821]

[0822] Step 1: Synthesis of Compound 69

[0823] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 69-a (9.06 mg, 0.06 mmol), yielding 13 mg of the pale yellow product compound 69. MS m / z (ESI): 478.22 [M+H] + .

[0824] 1 H NMR (400MHz, DMSO) δ10.24(s,1H),8.17(dd,J=5.7,2.5Hz,1H),8.03–7.92(m,2H),7.51(t,J=9. 1Hz,1H),7.22(d,J=6.9Hz,2H),3.39(s,3H),2.22(s,3H),2.01(d,J=12.2Hz,9H),1.63(s,6H).

[0825] Example 70: Preparation of Compound 70

[0826]

[0827] Step 1: Synthesis of Compound 70

[0828] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 70-a (6.18 mg, 0.06 mmol), yielding 9 mg of the pale yellow product compound 70. MS m / z (ESI): 430.18 [M+H] + .

[0829] 1 H NMR (400MHz, DMSO) δ10.27(s,1H),8.17(dd,J=5.7,2.6Hz,1H),8.10(s,1H),7.95(ddd,J=9.0,4.7,2.7Hz,1H),7. 50(t,J=9.1Hz,1H),7.25(d,J=7.2Hz,2H),3.52(t,J=6.9Hz,2H),2.20(s,3H),1.84(t,J=6.9Hz,2H),1.32(s,6H).

[0830] Example 71 Preparation of Compound 71

[0831]

[0832] Step 1: Synthesis of Compound 71

[0833] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 71-a (24.5 mg, 0.17 mmol), yielding a yellow solid, compound 71 (5.9 mg, 0.01 mmol). MS m / z (ESI): 468.20 [M+H] + .

[0834] 1 H NMR (400MHz, DMSO) δ10.34(s,1H),9.76(s,1H),8.19(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.8,2.6 Hz,1H),7.54(t,J=9.1Hz,1H),7.40(d,J=6.2Hz,2H),4.80(d,J=2.1Hz,4H),3.42(s,3H),2.20(s,3H).

[0835] Example 72 Preparation of Compound 72

[0836]

[0837] Step 1: Synthesis of Compound 72

[0838] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 72-a (23.0 mg, 0.17 mmol), yielding a yellow solid, compound 72 (8.6 mg, 0.02 mmol). MS m / z (ESI): 458.26 [M+H] + .

[0839] 1 H NMR (400MHz, DMSO) δ10.31(s,1H),9.48(s,1H),8.19(dd,J=5.8,2.6Hz,1H),7.96(ddt,J=9.4,4.9,2.4Hz,1 H),7.53(t,J=9.2Hz,1H),7.35(d,J=6.3Hz,1H),3.49(s,1H),3.42(s,3H),3.17–3.06(m,4H),2.19(s,3H).

[0840] Example 73 Preparation of Compound 73

[0841]

[0842] Step 1: Synthesis of Compound 73

[0843] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 73-a (7.80 mg, 0.06 mmol), yielding 11 mg of the pale yellow product compound 73. MS m / z (ESI): 456.20 [M+H] + .

[0844] 1 H NMR (400MHz, DMSO) δ10.24(s,1H),8.46(d,J=7.6Hz,1H),8.16(dd,J=5.7,2.4Hz,1H),7.94(m,1H),7.51(t,J=9.1Hz, 1H),7.25(d,J=7.1Hz,1H),3.75–3.61(m,1H),3.39(s,3H),3.19(s,3H),2.15(s,3H),1.84–1.74(m,2H),1.52(m,6H).

[0845] Example 74 Preparation of Compound 74

[0846]

[0847] Step 1: Synthesis of Compound 74

[0848] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 74-a (19.2 mg, 0.15 mmol), yielding a yellow solid, compound 74 (4 mg, 0.01 mmol). MS m / z (ESI): 455.14 [M+H] + .

[0849] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.61(s,1H),8.19(dd,J=3.8,2.0Hz,1H),7.96(ddt,J=9.3,4.7,2.4Hz,1H),7.53(t,J=9 .1Hz,1H),7.31(d,J=6.8Hz,1H),7.05(s,1H),6.74(s,1H),3.41(s,3H),2.20(s,3H),2.14–1.98(m,4H),1.66(t,J=6.8Hz,4H)

[0850] Example 75 Preparation of Compound 75

[0851]

[0852] Step 1: Synthesis of Compound 75

[0853] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 75-a (4.2 mg, 0.06 mmol), yielding 7 mg of the pale yellow product compound 75. MS m / z (ESI): 398.41 [M+H] + .

[0854] 1 H NMR (400MHz, DMSO) δ10.27(s,1H),8.80(d,J=7.8Hz,1H),8.15(dd,J=5.7,2.6Hz,1H),7.93(s,1H),7.50(t,J=9.1Hz,1H),7. 28(s,2H),4.27(s,1H),2.17(dd,J=6.8,3.7Hz,2H),2.12(s,3H),1.97(dd,J=15.0,5.8Hz,2H),1.65(dd,J=9.5,4.1Hz,2H).

[0855] Example 76 Preparation of Compound 76

[0856]

[0857] Step 1: Synthesis of Compound 76

[0858] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 76-a (30.3 mg, 0.17 mmol), yielding a yellow solid, compound 76 (15.1 mg, 0.03 mmol). MS m / z (ESI): 501.10 [M+H] + .

[0859] 1 H NMR (400MHz, DMSO) δ14.92(s,1H),10.29(s,1H),9.60(s,1H),8.17(dd,J=5.8,2.7Hz,1H),7.94(ddd,J=9.3,4.9,2.7 Hz,1H),7.77(s,1H),7.52(t,J=9.1Hz,1H),7.33(d,J=6.5Hz,2H),3.40(s,3H),3.26(d,J=12.7Hz,4H),2.05(s,3H).

[0860] Example 77 Preparation of Compound 77

[0861]

[0862] Step 1: Synthesis of compound 77-b

[0863] The procedure was the same as for the synthesis of compound 1-d, except that 1-b was replaced with 16-b (5 g, 1.58 mmol) and 1-c was replaced with 77-a, yielding 5.5 g of a brownish-yellow solid compound 77-b. MS m / z (ESI): 289.12 [M+H] + .

[0864] Step 2: Synthesis of compound 77-d

[0865] 77-b (5 g, 17.3 mmol) was added to a reaction flask and dissolved in dichloromethane (100 mL). Then, 2-b (7 g, 51.9 mmol) and aluminum trichloride (7.8 g, 51.9 mmol) were added under ice-water bath conditions. After reacting at room temperature for approximately 2 hours, the reaction solution was quenched with water. The dichloromethane was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 5 g of a brown solid compound, 77-d. MS m / z (ESI): 389.12 [M+H] + .

[0866] Step 3: Synthesis of compound 77-e

[0867] 77-d (5 g, 12.8 mmol) and N-fluorobis(benzenesulfonamide) (22.9 g, 72.77 mmol) were added to a reaction flask, followed by ethyl acetate (250 mL) and then 2,2,6,6-tetramethylpiperidine oxide (5.7 g, 36.38 mmol). The reaction was carried out under nitrogen protection at 50 °C for 12 hours. The mixture was then concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1-20:1). The final product was purified by C18 column chromatography with an eluent ratio of 60% (acetonitrile):40% (ultrapure water [0.05% / L formic acid]) to 80% (acetonitrile):20% (ultrapure water [0.05% / L formic acid]). The purified product was collected and concentrated under reduced pressure to obtain an orange-yellow solid compound 77-e (8 g, 3.64 mmol). MS m / z (ESI): 684.15 [M+H] + .

[0868] Step 4: Synthesis of compound 77-f

[0869] 77-e (3 g, 4.39 mmol) was added to a reaction flask and dissolved in 20 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (1.94 mL, 21.95 mmol) was then added. The mixture was heated to 80 °C and stirred for 20 minutes. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate aqueous solution. The organic phase was collected, concentrated, and purified by reverse-phase C18 column chromatography. The eluent ratio was 60% (acetonitrile):40% (ultrapure water [0.05% / L formic acid]) - 80% (acetonitrile):20% (ultrapure water [0.05% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give a yellow solid compound 77-f (0.6 g, 1.48 mmol). MS m / z (ESI): 404.31 [M+H] + .

[0870] Step 5: Synthesis of compound 77-g

[0871] 77-f (0.6 g, 1.48 mmol) was dissolved in a mixed solvent of ethanol (9 mL) and water (3 mL). Sodium hydroxide (0.3 g, 7.43 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for about 1 hour. After the starting material was consumed by LCMS monitoring, the pH was adjusted to about 5, and the ethanol was removed by concentration under reduced pressure. The residue was purified by C18 column chromatography with an eluent ratio of 30% (acetonitrile):70% (ultrapure water [0.05% / L formic acid]) - 60% (acetonitrile):40% (ultrapure water [0.05% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give an orange-yellow solid compound 77-g (300 mg, 0.8 mmol). MS m / z (ESI): 376.32 [M+H] + .

[0872] Step 6: Synthesis of Compound 77

[0873] 77-g (60 mg, 0.18 mmol) and 77-h (39.2 mg, 0.31 mmol) were added to a reaction flask, dissolved in N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (61.7 mg, 0.47 mmol). The mixture was stirred in an ice-water bath for one minute, and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (121.2 mg, 0.31 mmol) was added. The reaction mixture was then stirred in an ice-water bath for half an hour. The reaction solution was directly purified by a C18 column with an eluent ratio of 20% (acetonitrile):80% (ultrapure water [0.05% / L formic acid]) - 50% (acetonitrile):50% (ultrapure water [0.05% / L formic acid]). The purified product was collected and concentrated under reduced pressure to obtain a yellow solid compound 77 (10 mg, 0.002 mmol). MS m / z (ESI): 445.11 [M+H] + .

[0874] 1 H NMR (400MHz, DMSO) δ10.45 (s, 1H), 9.08 (s, 1H), 7.63 (dd, J = 10.4, 6.5Hz, 2H), 7.46 (d, J=4.5Hz,2H),4.72(d,J=6.2Hz,2H),4.38(d,J=6.2Hz,2H),3.47(s,3H),1.60(s,3H).

[0875] Example 78 Preparation of Compound 78

[0876]

[0877] Step 1: Synthesis of Compound 78

[0878] The procedure was the same as for the synthesis of compound 77, except that 77-h was replaced with 78-a (39.2 mg, 0.31 mmol), yielding a yellow solid compound 78 (12 mg, 0.002 mmol). MS m / z (ESI): 445.11 [M+H] + .

[0879] 1 H NMR (400MHz, DMSO) δ10.42(s,1H),8.80(d,J=6.8Hz,1H),7.67–7.58(m,2H),7.43(d,J=4.8Hz,2H),5.05(d,J=5.5H z,1H),4.26(q,J=5.8Hz,2H),3.46(s,3H),2.23(ddd,J=11.6,6.8,4.5Hz,2H),2.13(ddd,J=12.6,8.0,5.2Hz,2H).

[0880] Example 79 Preparation of Compound 79

[0881]

[0882] Step 1: Synthesis of Compound 79

[0883] The procedure was the same as for the synthesis of compound 50, except that 50-d was replaced with 79-a (44.6 mg, 0.20 mmol), yielding a yellow solid, compound 79 (14.5 mg, 0.02 mmol). MS m / z (ESI): 521.19 [M+H] + .

[0884] 1H NMR (400MHz, DMSO) δ10.48(s,1H),9.61(s,1H),8.37(s,1H),8.19(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9. 2,4.9,2.7Hz,1H),7.76(s,1H),7.55(t,J=9.1Hz,1H),7.47(s,1H),3.47(s,3H),3.27(d,J=12.3Hz,4H).

[0885] Example 80: Preparation of Compound 80

[0886]

[0887] Step 1: Synthesis of Compound 80

[0888] The procedure was the same as for the synthesis of compound 20, except that 20-d was replaced with 80-a (39.2 mg, 0.31 mmol), yielding a yellow solid, compound 80 (16.9 mg, 0.04 mmol). MS m / z (ESI): 425.22 [M+H] + .

[0889] 1 H NMR (400MHz, DMSO) δ10.28(s,1H),9.09(s,1H),7.65–7.56(m,2H),7.34(d,J=6.7Hz,2H ),4.68(d,J=6.3Hz,2H),4.38(d,J=6.3Hz,2H),3.41(s,3H),2.20(s,3H),1.59(s,3H).

[0890] Example 81 Preparation of Compound 81

[0891]

[0892] Step 1: Synthesis of Compound 81

[0893] The procedure was the same as for the synthesis of compound 20, except that 20-d was replaced with 81-a (39.2 mg, 0.31 mmol), yielding a yellow solid compound 81 (12 mg, 0.03 mmol). MS m / z (ESI): 425.22 [M+H] + .

[0894] 1H NMR (400MHz, DMSO) δ10.25(s,1H),8.84(d,J=7.0Hz,1H),7.60(dd,J=10.4,6.5Hz,2H),7.30( d,J=6.9Hz,2H),5.05(d,J=5.5Hz,1H),4.28(h,J=6.4Hz,2H),3.40(s,3H),2.25–2.10(m,7H).

[0895] Example 82 Preparation of Compound 82

[0896]

[0897] Step 1: Synthesis of Compound 82

[0898] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 82-a (8.5 mg, 0.07 mmol), yielding a yellow solid, compound 82 (5 mg, 0.01 mmol). MS m / z (ESI): 409.19 [M+H] + .

[0899] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.60(s,1H),8.20(ddd,J=5.9,2.7,1.3Hz,1H),7.97(ddt,J=9.4,4.7,2.2Hz ,1H),7.54(t,J=9.1Hz,1H),7.38(d,J=5.9Hz,2H),3.41(s,3H),2.14(s,3H),1.63–1.56(m,2H),1.25–1.18(m,2H).

[0900] Example 83 Preparation of compound 83

[0901]

[0902] Step 1: Synthesis of Compound 83

[0903] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 83-a (35.1 mg, 0.29 mmol), yielding a yellow solid, compound 83 (27.5 mg, 0.06 mmol). MS m / z (ESI): 412.25 [M+H] + .

[0904] 1H NMR (400MHz, DMSO) δ8.59 (d, J=8.3Hz, 1H), 8.27–8.16 (m, 1H), 7.96 (ddt, J=9.6, 4.9,2.3Hz,1H),7.53(t,J=9.1Hz,1H),7.30(d,J=7.1Hz,1H),3.41(s,3H),3.29 (d,J=6.9Hz,1H),2.21(s,3H),1.18(d,J=6.7Hz,3H),0.92(dtd,J=13.1,8.3,4. 7Hz, 1H), 0.41 (dtd, J=16.9, 8.6, 4.4Hz, 2H), 0.26 (ddt, J=26.2, 9.0, 4.3Hz, 2H).

[0905] Example 84 Preparation of Compound 84

[0906]

[0907] Step 1: Synthesis of Compound 84

[0908] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 84-a (12.6 mg, 0.15 mmol), yielding a yellow solid compound 84 (15 mg, 0.04 mmol). MS m / z (ESI): 411.16 [M+H] + .

[0909] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.26(s,1H),8.21(dd,J=7.3,4.1Hz,1H),7.98(ddd,J=9.1,4 .7,2.4Hz,1H),7.54(t,J=9.1Hz,1H),7.35(d,J=6.0Hz,1H),3.42(s,3H),2.19(s,3H),1.66(s,6H).

[0910] Example 85 Preparation of Compound 85

[0911]

[0912] Step 1: Synthesis of Compound 85

[0913] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 85-a (30.5 mg, 0.29 mmol), yielding a yellow solid, compound 85 (18.3 mg, 0.04 mmol). MS m / z (ESI): 396.23 [M+H] + .

[0914] 1 H NMR (400MHz, DMSO) δ8.33(s,1H),8.18(dd,J=5.9,2.6Hz,1H),7.96(ddt,J=9.3,4.6,2.1Hz,1H),7.53(t,J=9.1Hz,1 H),7.31(d,J=6.6Hz,1H),4.73–4.64(m,1H),3.41(s,3H),3.22(d,J=2.3Hz,1H),2.16(s,3H),1.36(d,J=6.9Hz,3H).

[0915] Example 86 Preparation of Compound 86

[0916]

[0917] Step 1: Synthesis of Compound 86

[0918] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 86-a (5.1 mg, 0.06 mmol), yielding 10 mg of the pale yellow product compound 86. MS m / z (ESI): 407.15 [M+H] + .

[0919] 1 H NMR (400MHz, DMSO) δ10.16(d,J=23.3Hz,1H),9.16–8.98(m,1H),8.27(d,J=39.1Hz,1H),7.83(ddd,J=14.7,8.8,6 .8Hz,1H),7.46–7.19(m,3H),4.65(d,J=6.3Hz,2H),4.36(d,J=6.3Hz,2H),3.39(s,3H),2.18(s,3H),1.56(s,3H).

[0920] Example 87 Preparation of Compound 87

[0921]

[0922] Step 1: Synthesis of Compound 87

[0923] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 87-a (39.2 mg, 0.29 mmol), yielding a yellow solid, compound 87 (14.6 mg, 0.03 mmol). MS m / z (ESI): 426.25 [M+H] + .

[0924] 1H NMR (400MHz, DMSO) δ10.27(s,1H),8.35(d,J=8.5Hz,1H),8.18(dd,J=5.8,2.7Hz,1H),7.96(ddt,J=9.3,4.8,2.3Hz,1H),7.53(t,J=9.1Hz,1H), 7.28(s,1H),3.90–3.80(m,1H),3.41(s,3H),2.32(s,1H),2.19(s,3H), 2.00–1.89(m,2H),1.76(tt,J=10.8,6.7Hz,4H),1.00(d,J=6.6Hz,3H).

[0925] Example 88: Preparation of Compound 88

[0926]

[0927] Step 1: Synthesis of Compound 88

[0928] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 88-a (50.8 mg, 0.29 mmol), yielding a yellow solid compound 88 (13.3 mg, 0.03 mmol). MS m / z (ESI): 466.24 [M+H] + .

[0929] 1 H NMR (400MHz, DMSO) δ9.38(d,J=9.0Hz,1H),8.19(ddd,J=5.8,2.7,1.4Hz,1H),7.97(ddt,J=9.4,4.8,2.3Hz,1H),7.54(t,J=9.1Hz,1H),7.35(d, J=6.4Hz,1H),4.04(q,J=7.8Hz,1H),3.42(s,3H),2.16(s,3H),1.21–1.10(m,1H),0.62(dddd,J=36.1,16.3,8.9,4.6Hz,3H),0.38–0.29(m,1H).

[0930] Example 89 Preparation of Compound 89

[0931]

[0932] Step 1: Synthesis of compound 89-b

[0933] The procedure was the same as for the synthesis of compound 1-d, except that 1-c was replaced with 89-a (2.99 g, 23.9 mmol), yielding the reddish-brown solid compound 89-b (1.6 g, 6.50 mmol). MS m / z (ESI): 247.16 [M+H] + .

[0934] Step 2: Synthesis of compound 89-c

[0935] The procedure was the same as for the synthesis of compound 3-a, except that 1-d was replaced with 89-b (2.99 g, 23.9 mmol), yielding the reddish-brown solid compound 89-c (1.1 g, 3.17 mmol). MS m / z (ESI): 347.22 [M+H] + .

[0936] Step 3: Synthesis of compound 89-d

[0937] The procedure was the same as for the synthesis of compound 2-g, except that 2-f was replaced with 89-c (1.1 g, 3.17 mmol), yielding the reddish-brown solid compound 89-d (1.3 g, 2.03 mmol). MS m / z (ESI): 642.21 [M+H] + .

[0938] Step 4: Synthesis of compound 89-e

[0939] The procedure was the same as for the synthesis of compound 2, except that 2-g was replaced with 89-d (1.3 g, 2.03 mmol), yielding the yellow solid compound 89-e (0.16 g, 0.44 mmol). MS m / z (ESI): 362.22 [M+H] + .

[0940] Step 5: Synthesis of compound 89-f

[0941] The procedure was the same as for the synthesis of compound 8-c, except that 8-b was replaced with 89-e (0.16 g, 0.44 mmol), yielding the yellow solid compound 89-f (0.10 g, 0.30 mmol). MS m / z (ESI): 334.29 [M+H] + .

[0942] Step 6: Synthesis of Compound 89

[0943] The procedure was the same as for the synthesis of compound 8, except that 8-c was replaced with 89-f (30 mg, 0.10 mmol) and 8-d was replaced with 2-a, yielding a yellow solid compound 89 (2.4 mg, 0.05 mmol). MS m / z (ESI): 429.16 [M+H] + .

[0944] 1 H NMR (400MHz, DMSO) δ8.32(s,1H),7.65–7.59(m,1H),7.55–7.47(m,1H),7.32(d,J=6.7Hz,1H),7.10(t,J= 9.2Hz, 1H), 4.71 (q, J = 7.3Hz, 1H), 3.40 (s, 3H), 2.23 (d, J = 1.9Hz, 3H), 2.12 (s, 3H), 1.31 (d, J = 7.0Hz, 3H).

[0945] Example 90: Preparation of Compound 90

[0946]

[0947] Step 1: Synthesis of compound 90-b

[0948] Add 90-a (13 mL, 116.35 mmol) to a three-necked flask, add dry tetrahydrofuran (140 mL), and stir at -78°C for 10 minutes under nitrogen protection. Then, slowly add methyl-D3-magnesium iodide (65 mL, 1 M in Et2O) dropwise. After stirring at -78°C for 2 hours, slowly add 1 M HCl aqueous solution (35 mL) to quench the reaction. After the reaction is brought to room temperature, add saturated saline solution (100 mL), separate the layers, and concentrate the upper organic phase to one-third of its volume. This concentrate is then used directly in the next step.

[0949] Step 2: Synthesis of compound 90-c

[0950] 17-b (7 g, 32.11 mmol) was dissolved in a mixed solvent of toluene (160 mL) and water (40 mL). 90-b (64 mL, 64 mmol), potassium carbonate (13.7 g, 96.33 mmol), Pd(OAc)₂ (0.7 g, 3.21 mmol), and Ruphos (0.7 g, 3.21 mmol) were added. The mixture was heated to 87 °C and stirred overnight under nitrogen protection. Saturated brine (200 mL) was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (PE / EA = 9 / 1) to give a pale yellow oily liquid, 90-c (3.6 g, 23.05 mmol). MS m / z (ESI): 157.14 [M+H] + .

[0951] Step 3: Synthesis of compound 90-d

[0952] 90-c (3.6 g, 23.05 mmol) and 4-b (3.8 g, 27.66 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (80 mL). The mixture was stirred in an ice-water bath for five minutes under nitrogen protection. Then, bis(trimethylsilylaminolithium) (69.14 mL, 69.14 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction solution was then quenched with ice water (100 mL), and saturated brine (100 mL) and ethyl acetate (100 mL) were added. The mixture was separated, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then a small amount of ethyl acetate was added to the resulting solid to form a slurry. The slurry was filtered and washed with a small amount of ethyl acetate to obtain a white solid, 90-d (4 g, 15.37 mmol). MS m / z (ESI): 261.18 [M+H] + .

[0953] Step 4: Synthesis of compound 90-e

[0954] 90-d (4 g, 15.37 mmol) was added to a reaction flask, followed by dichloromethane (50 mL). Then, 2-b (8.60 mL, 76.83 mmol) was slowly added under an ice-water bath. Aluminum trichloride (14.3 g, 107.57 mmol) was added in portions. The reaction was carried out at room temperature for 4 hours under nitrogen protection. The reaction solution was then slowly poured into ice water (100 mL), resulting in the precipitation of a large amount of white solid. The mixture was filtered, and the white filter cake was evaporated to dryness. The filtrate was separated, and the organic phase was washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The filter cakes were combined to obtain a white solid, 90-e (5 g, 13.87 mmol). MS m / z (ESI): 361.18 [M+H] + .

[0955] Step 5: Synthesis of compound 90-f

[0956] 90-e (3.5 g, 9.71 mmol) and NFSI (61.2 g, 194.23 mmol) were added to a reaction flask, followed by ethyl acetate (50 mL) and TEMPO (15.2 g, 97.11 mmol). The mixture was reacted at 50 °C for 18 hours under nitrogen protection. The reaction mixture was then concentrated and purified by C18 column chromatography using an eluent ratio of 80% (acetonitrile):20% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to obtain an orange-yellow solid, 90-f (6.36 g, 9.70 mmol). MS m / z (ESI): 656.25 [M+H] + .

[0957] Step 6: Synthesis of compound 90-g

[0958] 90-f (6.36 g, 9.70 mmol) was added to a reaction flask and dissolved in 1,2-dichloroethane (60 mL). Trifluoromethanesulfonic acid (5.14 mL, 58.20 mmol) was then added. The mixture was heated to 80 °C and stirred for 20 minutes. The solution was then concentrated at room temperature to obtain a black, oily crude product. This product was dissolved in ethyl acetate (100 mL), and saturated sodium bicarbonate aqueous solution (30 mL) was added under ice-water bath conditions. The mixture was separated, and the organic phase was washed with saturated brine (100 mL), evaporated to dryness, and purified by C18 column chromatography. The eluent ratio was 60% (acetonitrile):40% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to obtain an orange-yellow solid, 90-g (1.1 g, 2.93 mmol). MS m / z (ESI): 376.25 [M+H] + .

[0959] Step 7: Synthesis of compound 90-h

[0960] 90-g (200 mg, 0.53 mmol) was dissolved in a mixed solvent of ethanol (9 mL) and water (3 mL). Sodium hydroxide (128 mg, 3.20 mmol) was added under ice-water bath conditions, and the reaction was carried out at room temperature for approximately 1 hour. After the starting material was consumed, the pH was adjusted to approximately 5, and the mixture was concentrated. A solid precipitated, which was filtered, and the filter cake was evaporated to dryness to obtain a yellowish-brown solid, 90-h (150 mg, 0.43 mmol). MS m / z (ESI): 348.24 [M+H] + .

[0961] Step 8: Synthesis of Compound 90

[0962] Add 90-h (60 mg, 0.12 mmol) and 2-a (21.7 mg, 0.15 mmol) to a reaction flask, dissolve in N,N-dimethylformamide (2 mL), then add N,N-diisopropylethylamine (0.06 mL, 0.36 mmol). Stir for 1 minute in an ice-water bath, then add HATU (55.2 mg, 0.15 mmol) and stir for 20 minutes in an ice-water bath. Purify the reaction solution directly using a C18 column with an eluent ratio of 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). Collect the purified product, lyophilize to obtain a yellow solid compound 90 (25 mg, 0.06 mmol). MS m / z (ESI): 443.12 [M+H] + .

[0963] 1H NMR (400MHz, DMSO) δ10.32(s,1H),9.24(d,J=8.8Hz,1H),8.18(dd,J=5.8,2.7Hz,1H),7.96(ddd,J=9.2,4.9 ,2.7Hz,1H),7.53(t,J=9.1Hz,1H),7.36(s,2H),4.71(h,J=7.5Hz,1H),3.42(s,3H),1.31(d,J=7.0Hz,3H).

[0964] Example 91 Preparation of compound 91

[0965]

[0966] Steps: Synthesis of Compound 91

[0967] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 91-a (10.02 mg, 0.06 mmol), yielding 13 mg of the pale yellow product compound 91. MS m / z (ESI): 494.21 [M+H] + .

[0968] 1H NMR (400MHz, DMSO) δ10.24(s,1H),8.17(dd,J=5.7,2.6Hz,1H),8.09(s,1H),8.00–7.90(m,1H),7.50(t,J=9.1Hz,1H),7.22 (d,J=7.2Hz,2H),4.45(d,J=55.4Hz,1H),3.39(s,3H),2.21(s,3H),2.15(s,2H),1.88(d,J=10.0Hz,6H),1.60–1.39(m,6H).

[0969] Example 92 Preparation of compound 92

[0970]

[0971] Step 1: Synthesis of Compound 92

[0972] The procedure was the same as for the synthesis of compound 77, except that 77-h was replaced with 2-a (31.7 g, 0.21 mmol), yielding a yellow solid compound 92 (20.3 mg, 0.04 mmol). MS m / z (ESI): 471.15 [M+H] + .

[0973] 1H NMR (400MHz, DMSO) δ10.47(s,1H),9.22(d,J=8.7Hz,1H),7.62(dd,J=10.3,6.4 Hz,2H),7.48(s,2H),4.69(h,J=7.6Hz,1H),3.47(s,3H),1.30(d,J=7.0Hz,3H).

[0974] Example 93 Preparation of compound 93

[0975]

[0976] Steps: Synthesis of Compound 93

[0977] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 93-a (7.84 mg, 0.07 mmol), yielding 15 mg of the pale yellow product compound 93. MS m / z (ESI): 439.13 [M+H] + .

[0978] 1 HNMR (400MHz, DMSO) δ11.04(s,1H),10.32(s,1H),8.51(s,1H),8.28–8.19(m,1H),8.16(dd,J=5.7,2.6Hz,1H),7.9 8–7.88(m,1H),7.50(t,J=9.1Hz,1H),7.42(d,J=5.5Hz,2H),7.22(dd,J=8.8,3.1Hz,1H),3.42(s,3H),2.12(s,3H).

[0979] Example 94 Preparation of Compound 94

[0980]

[0981] Step 1: Synthesis of Compound 94

[0982] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 94-a (8.1 mg, 0.09 mmol), yielding a yellow solid, compound 94 (15 mg, 0.03 mmol). MS m / z (ESI): 416.13 [M+H] + .

[0983] 1H NMR(400MHz, DMSO-d6)δ10.26(s,1H),8.19(dd,J=5.8,2.7Hz,1H),8.01-7.91(m,2H),7.53(t ,J=9.1Hz,1H),7.29(s,2H),4.86(s,1H),3.45(s,2H),3.41(s,3H),2.23(s,3H),1.29(s,6H).

[0984] Example 95 Preparation of Compound 95

[0985]

[0986] Step 1: Synthesis of Compound 95

[0987] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 95-a (12.4 mg, 0.09 mmol), yielding a yellow solid, compound 95 (15 mg, 0.03 mmol). MS m / z (ESI): 428.11 [M+H] + .

[0988] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.42(s,1H),8.19(dd,J=5.8,2.7Hz,1H),8.02-7.93(m,1H),7.53(t,J=9.1Hz,1H),7.29(s,2 H),4.85(s,1H),3.58(s,2H),3.42(s,3H),2.37-2.25(m,2H),2.24(s,3H),2.17-2.07(m,2H),1.91-1.79(m,1H),1.78-1.67(m,1H).

[0989] Example 96 Preparation of Compound 96

[0990]

[0991] Step 1: Synthesis of Compound 96

[0992] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 96-a (10.5 mg, 0.09 mmol), yielding a yellow solid, compound 96 (12 mg, 0.03 mmol). MS m / z (ESI): 442.23 [M+H] + .

[0993] 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.23-8.17(m,1H),8.08(s,1H),8.01-7.93(m,1H),7.53(t,J=9.1Hz,1H),7.27( d,J=7.4Hz,1H),3.58-3.52(m,2H),3.41(s,3H),2.23(s,3H),2.01-1.91(m,2H),1.79-1.65(m,4H),1.63-1.54(m,2H).

[0994] Example 97 Preparation of Compound 97

[0995]

[0996] Step 1: Synthesis of Compound 97

[0997] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 97-a (15.2 mg, 0.12 mmol), yielding a yellow solid, compound 97 (20.5 mg, 0.04 mmol). MS m / z (ESI): 458.16 [M+H] + .

[0998] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.19(dd,J=5.8,2.7Hz,1H),8.06(s,1H),7.97(ddd,J=9.3,4.9,2.7Hz,1H),7.53(t,J=9.1Hz,1H),7.27(d, J=7.2Hz,2H),4.83(s,1H),3.72–3.64(m,2H),3.61–3.53(m,4H),3.42(s ,3H),2.24(s,3H),2.04(d,J=13.4Hz,2H),1.68(td,J=12.4,4.6Hz,2H).

[0999] Example 98: Preparation of Compound 98

[1000]

[1001] Step 1: Synthesis of Compound 98

[1002] The procedure was the same as for the synthesis of compound 50, except that 50-d was replaced with 3-c (5.50 mg, 0.10 mmol), yielding 10 mg of the pale yellow product compound 98. MS m / z (ESI): 402.07 [M+H] + .

[1003] 1 H NMR (400MHz, DMSO) δ8.20(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.9,2.7Hz,1H),7.55(t,J=9.1Hz,1 H),7.43(d,J=4.2Hz,1H),3.99(dd,J=6.2,2.6Hz,2H),3.47(s,3H),3.15(t,J=2.5Hz,1H),2.86(s,3H).

[1004] Example 99: Preparation of Compound 99

[1005]

[1006] Step 1: Synthesis of Compound 99

[1007] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 99-a (18 mg, 0.17 mmol), yielding a yellow solid, compound 99 (13 mg, 0.03 mmol). MS m / z (ESI): 430.31 [M+H] + .

[1008] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.44(t,J=6.2Hz,1H),8.24–8.09(m,1H),8.02–7.88(m,1H),7.53(t,J=9.1Hz,1H) ,7.39–7.27(m,2H),4.56(t,J=5.7Hz,1H),3.41(s,3H),3.20–3.14(m,2H),3.10–3.04(m,2H),2.18(s,3H),0.84(s,6H).

[1009] Example 100: Preparation of Compound 100

[1010]

[1011] Step 1: Synthesis of Compound 100

[1012] The procedure was the same as for the synthesis of compound 89, except that 2-a was replaced with 3-c (5.50 mg, 0.10 mmol), yielding 12 mg of the pale yellow product compound 100. MS m / z (ESI): 371.14 [M+H] + .

[1013] 1H NMR (400MHz, DMSO) δ7.62 (d, J=7.1Hz, 1H), 7.49 (dd, J=5.8, 3.3Hz, 1H), 7.28 (d, J=7.0Hz, 1H), 7.10 (t, J= 9.2Hz, 1H), 3.98 (q, J = 2.8Hz, 2H), 3.40 (s, 3H), 3.15 (t, J = 2.5Hz, 1H), 2.23 (d, J = 1.9Hz, 3H), 2.13 (s, 3H).

[1014] Example 101 Preparation of Compound 101

[1015]

[1016] Step 1: Synthesis of Compound 101

[1017] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 101-a (28.4 mg, 0.22 mmol), yielding a yellow solid compound 101 (11 mg, 0.02 mmol). MS m / z (ESI): 421.40 [M+H] + .

[1018] 1 H NMR(400MHz, DMSO-d6)δ10.96(s,1H),10.32(s,1H),8.86(d,J=2.3Hz,1H),8.43–8.34(m,1H),8.26–8.17(m,1H),8.15–8.14 (m,1H),8.12(dd,J=2.7,1.5Hz,1H),8.00–7.91(m,1H),7.53(t,J=9.2Hz,1H),7.48–7.33(m,2H),3.44(s,3H),2.14(s,3H).

[1019] Example 102 Preparation of compound 102

[1020]

[1021] Step 1: Synthesis of compound 102-a

[1022] The procedure was the same as for the synthesis of compound 90-d, except that 4-b was replaced with 1-c (1.7 g, 13.44 mmol), yielding a white solid compound 102-a (2 g, 7.9 mmol). MS m / z (ESI): 254.14 [M+H] + .

[1023] Step 2: Synthesis of compound 102-b

[1024] The procedure was the same as for the synthesis of compound 90-e, except that 90-d was replaced with 102-a (2 g, 7.9 mmol), yielding a white solid compound 102-b (2.7 g, 7.64 mmol). MS m / z (ESI): 354.14 [M+H] + .

[1025] Step 3: Synthesis of compound 102-c

[1026] The procedure was the same as for the synthesis of compound 90-f, except that 90-e was replaced with 102-b (1 g, 2.83 mmol), yielding the white solid compound 102-c (1.8 g, 2.77 mmol). MS m / z (ESI): 649.28 [M+H] + .

[1027] Step 4: Synthesis of compound 102-d

[1028] The procedure was the same as for the synthesis of compound 90-g, except that 90-f was replaced with 102-c (1.8 g, 2.77 mmol), yielding a white solid compound 102-d (0.5 g, 1.36 mmol). MS m / z (ESI): 369.46 [M+H] + .

[1029] Step 5: Synthesis of compound 102-e

[1030] The procedure was the same as for the synthesis of compound 90-h, except that 90-g was replaced with 102-d (100 mg, 0.27 mmol), yielding a white solid compound 102-e (50 mg, 0.15 mmol). MS m / z (ESI): 341.11 [M+H] + .

[1031] Step 6: Synthesis of Compound 102

[1032] The procedure was the same as for the synthesis of compound 90, except that 90-h was replaced with 102-e (50 mg, 0.15 mmol), yielding a white solid compound 102 (50 mg, 0.15 mmol). MS m / z (ESI): 436.13 [M+H] + .

[1033] 1 H NMR (400MHz, DMSO) δ10.21 (s, 1H), 9.23 (d, J = 8.7Hz, 1H), 7.90–7.81 (m, 1H), 7.47–7 .38(m,2H),7.35(s,2H),4.71(h,J=7.6Hz,1H),3.41(s,3H),1.31(d,J=7.1Hz,3H).

[1034] Example 103 Preparation of compound 103

[1035]

[1036] Steps: Synthesis of Compound 103

[1037] The procedure was the same as for the synthesis of compound 8, except that 8-d was replaced with 51-a (12.18 mg, 0.07 mmol), yielding 16 mg of the pale yellow product compound 103. MS m / z (ESI): 494.14 [M+H] + .

[1038] 1 HNMR(400MHz,DMSO)δ10.19(s,1H),9.57(d,J=34.1Hz,1H),7.86–7.79(m,1H),7.75(s ,1H),7.39(dd,J=8.5,5.6Hz,2H),7.34(s,2H),3.43(s,3H),3.26(s,3H),2.02(s,3H).

[1039] Example 104 Preparation of compound 104

[1040]

[1041] Step 1: Synthesis of Compound 104

[1042] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 104-a (9.03 mg, 0.07 mmol), yielding 16 mg of the pale yellow product compound 104. MS m / z (ESI): 456.12 [M+H] + .

[1043] 1 HNMR (400MHz, DMSO) δ10.34(s,1H),9.22(d,J=8.9Hz,1H),8.17(dd,J=5.7,2.5Hz,1H),8.02–7.87(m,1H),7. 51(t,J=9.1Hz,1H),7.35(s,2H),4.71–4.50(m,1H),3.72(dd,J=4.8Hz,1H),3.66-3.62(m,1H),2.14(s,3H).

[1044] Example 105 Preparation of compound 105

[1045]

[1046] Step 1: Synthesis of compound 105-b

[1047] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 105-a (30.0 mg, 0.17 mmol), yielding 59 mg of the pale yellow product compound 105-b. MS m / z (ESI): 499.20 [M+H] + .

[1048] Step 2: Synthesis of Compound 105

[1049] Compound 105-b (59 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 5–6 with saturated sodium carbonate solution under ice-water bath conditions. The mixture was extracted three times with a mixed solvent of DCM / MeOH (10 / 10), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified to give 25 mg of a pale yellow solid, compound 105. MS m / z (ESI): 399.15 [M+H] + .

[1050] 1 HNMR (400MHz, DMSO) δ10.33(s,1H),9.27(d,J=7.0Hz,1H),8.17(dd,J=5.8,2.6Hz,1H),7.94(m,1H),7.51(t, J=9.1Hz,1H),7.34(s,2H),4.65(d,J=7.4Hz,1H),3.88–3.84(m,2H),3.71(s,2H),3.39(s,3H),2.11(s,3H).

[1051] Example 106 Preparation of Compound 106

[1052]

[1053] Step 1: Synthesis of Compound 106

[1054] Compound 105 (20 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and acetic anhydride (10.2 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to obtain a crude product, which was then purified to give 11 mg of a pale yellow solid, compound 106. MS m / z (ESI): 441.16 [M+H] + .

[1055] 1HNMR (400MHz, DMSO) δ10.29(s,1H),9.25(d,J=6.7Hz,1H),8.17(dd,J=5.8,2.6Hz,1H),7.94(m,1H),7.51(t,J=9.1Hz,1H),7.34(s,2H),4.58–4.47( m,1H),4.40(t,J=8.2Hz,1H),4.10(t,J=8.8Hz,1H),3.98(dd,J=8.5,5.3H z, 1H), 3.75 (dd, J = 9.7, 5.4Hz, 1H), 3.39 (s, 3H), 2.13 (s, 3H), 1.75 (s, 3H).

[1056] Example 107 Preparation of Compound 107

[1057]

[1058] Step 1: Synthesis of Compound 107

[1059] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 110-d (11.8 mg, 0.14 mmol), yielding a yellow solid compound 107 (18 mg, 0.04 mmol). MS m / z (ESI): 412.15 [M+H] + .

[1060] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.98(d,J=8.2Hz,1H),8.19(dd,J=5.8,2.6Hz,1H),7.96(m J=9.0,4.8,2.7Hz,1H),7.53(t,J=9.2Hz,1H),7.33(s,2H),5.16(s,1H),4.63(dd,J=12.8, 6.1Hz,1H),3.55(dd,J=13.6,8.3Hz,2H),3.41(s,3H),3.22(d,J=2.3Hz,1H),2.18(s,3H).

[1061] Example 108 Preparation of Compound 108

[1062]

[1063] Step 1: Synthesis of Compound 108

[1064] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 108-a (7.7 mg, 0.07 mmol), yielding a yellow solid compound 108 (15 mg, 0.03 mmol). MS m / z (ESI): 438.17 [M+H] + .

[1065] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.04(t,J=5.6Hz,1H),8.18(dd,J=5.8,2.6Hz,1H),7.95(m,J=9.1,4.8,2.7Hz,1H),7.53( t,J=9.2Hz,1H),7.32(s,2H),7.08(s,1H),6.80(d,J=1.0Hz,1H),4.43(d,J=5.6Hz,2H),3.68(s,3H),3.40(s,3H),2.07(s,3H).

[1066] Example 109 Preparation of compound 109

[1067]

[1068] Step 1: Synthesis of Compound 109

[1069] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 109-a (13.7 mg, 0.24 mmol), yielding a yellow solid compound 109 (7 mg, 0.02 mmol). MS m / z (ESI): 384.13 [M+H] + .

[1070] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.64(d,J=4.4Hz,1H),8.19(dd,J=5.7,2.6Hz,1H),8.04–7.86(m,1H),7.53(t,J =9.1Hz,1H),7.32(s,2H),3.40(s,3H),2.75(m,J=7.2,3.7Hz,1H),2.15(s,3H),0.72–0.67(m,2H),0.54–0.46(m,2H).

[1071] Example 110 Preparation of compound 110

[1072]

[1073] Step 1: Synthesis of compound 110-c

[1074] To a 40 mL vial, add 110-a (2 g, 8.72 mmol), 110-b (2 g, 10.47 mmol), K₂CO₃ (3.6 g, 26.17 mmol), and methanol (50 mL). Stir the resulting solution overnight at room temperature. Quench the reaction mixture with water (20 mL) and dilute with ethyl acetate (3 × 50 mL). Wash the mixture with brine (50 mL) and water (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography and concentrate under reduced pressure to give 1.6 g of a yellow oily substance, 110-c.

[1075] Step 2: Synthesis of compound 110-d

[1076] A solution of 110-c (1.6 g, 7.10 mmol), 1,4-dioxane (10 mL) in 4 M hydrochloric acid, and ethanol (20 mL) was stirred overnight at 60 °C. The mixture was concentrated under reduced pressure to give 780 mg of the yellowish-brown product compound 110-d.

[1077] Step 3: Synthesis of Compound 110

[1078] The procedure was the same as for the synthesis of compound 89, except that 2-a was replaced with 110-d (8.50 mg, 0.10 mmol), yielding 15 mg of the pale yellow product compound 110. MS m / z (ESI): 401.15 [M+H] + .

[1079] 1 HNMR(400MHz, DMSO)δ9.91(d,J=35.2Hz,1H),8.89(t,J=16.5Hz,1H),7.64–7.55(m,1H),7.53–7.40(m,1H),7.27(s,2H),7.1 2–7.00(m,1H),4.65–4.54(m,1H),3.52(dd,J=6.1,4.2Hz,2H),3.41(s,3H),3.19(d,J=2.1Hz,1H),2.21(s,3H),2.13(s,3H).

[1080] Example 111 Preparation of compound 111

[1081]

[1082] Step 1: Synthesis of Compound 111

[1083] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 111-a (6.78 mg, 0.07 mmol), yielding 13 mg of the pale yellow product compound 111. MS m / z (ESI): 424.13 [M+H]+ .

[1084] 1 HNMR (400MHz, DMSO) δ10.32(d,J=19.9Hz,1H),9.62(d,J=20.2Hz,1H),8.16(dt,J=13.9,6.9Hz,1H),7.99–7.90( m,1H),7.51(t,J=9.1Hz,1H),7.37(s,2H),4.71(dd,J=21.8,6.5Hz,4H),3.61(s,1H),3.40(s,3H),2.18(s,3H).

[1085] Example 112 Preparation of compound 112

[1086]

[1087] Step 1: Synthesis of Compound 112

[1088] Compound 34 (82 mg, 0.21 mmol), TMS-N3 (24.8 mg, 0.21 mmol), methanol (2 mL), acetonitrile (2 mL), water (1 mL), copper sulfate pentahydrate (8.1 mg, 0.03 mmol), sodium ascorbate (10.6 mg, 0.05 mmol), and potassium carbonate (29.7 mg, 0.21 mmol) were added to a two-necked flask. The mixture was then stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was then added... The organic layer was quenched in water, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by C18 column chromatography. The eluent ratio was 70% (acetonitrile):30% (ultrapure water [0.005% / L formic acid]) - 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected, concentrated under reduced pressure, and approximately 13 mg of a yellow solid compound 112 was obtained. MS m / z (ESI): 425.10 [M+H] + .

[1089] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.09(t,J=5.8Hz,1H),8.37(s,1H),8.17(dd,J=5.8,2.6Hz,1H),8.07–7 .87(m,1H),7.71(s,1H),7.52(t,J=9.1Hz,1H),7.33(s,2H),4.46(d,J=5.5Hz,2H),3.39(s,3H),2.06(s,3H).

[1090] Example 113 Preparation of compound 113

[1091]

[1092] Step 1: Synthesis of Compound 113

[1093] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 113-a (22.9 mg, 0.17 mmol), yielding a yellow solid compound 113 (11 mg, 0.02 mmol). MS m / z (ESI): 458.21 [M+H] + .

[1094] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.72(t,J=5.9Hz,1H),8.19(dd,J=5.8,2. 7Hz,1H),7.95(ddd,J=9.2,4.9,2.7Hz,1H),7.53(t,J=9.2Hz,1H),7.34(s,2H),4 .17(t,J=6.0Hz,1H),3.99(dd,J=8.4,6.2Hz,1H),3.68(dd,J=8.4,5.7Hz,1H),3 .39(s,3H),3.28(dd,J=11.4,5.9Hz,2H),2.15(s,3H),1.35(s,3H),1.26(s,3H).

[1095] Example 114 Preparation of Compound 114

[1096]

[1097] Step 1: Synthesis of Compound 114

[1098] Compound 113 (4 mg, 0.01 mmol) was added to a single-necked flask, followed by 0.5 mL of 1 N dilute hydrochloric acid. The mixture was stirred at room temperature for 10 min. The reaction solution was then purified directly through a C18 column using an eluent ratio of 70% (acetonitrile):30% (ultrapure water [0.005% / L formic acid]) to 50% (acetonitrile):50% (ultrapure water [0.005% / L formic acid]). The purified product was collected and concentrated under reduced pressure to give approximately 3 mg of a yellow solid, compound 114. MS m / z (ESI): 418.21 [M+H] + .

[1099] 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.47(t,J=5.7Hz,1H),8.19(dd,J=5.8,2.7Hz,1H),7.96(ddd,J=8.6,4.8,2.7Hz,1H),7.53(t,J=9.1 Hz,1H),7.34(s,2H),4.79(s,1H),4.60(s,1H),3.59(t,J=5.9Hz,2H),3.40(s,3H),3.30(d,J=9.3Hz,2H),3.15–3.07(m,1H),2.18(s,3H).

[1100] Example 115 Preparation of Compound 115

[1101]

[1102] Step 1: Synthesis of Compound 115

[1103] The procedure was the same as for the synthesis of compound 9, except that 9-e was replaced with 115-a (12.0 mg, 0.09 mmol), yielding a yellow solid compound 115 (8 mg, 0.02 mmol). MS m / z (ESI): 458.17 [M+H] + .

[1104] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.42(t,J=6.1Hz,1H),8.18(dd,J=5.8,2.7Hz,1H),8.00-7.91(m,1H),7.53(t,J=9.1Hz,1H) ,7.32(d,J=7.2Hz,1H),3.64-3.58(m,4H),3.41(s,3H),3.22(d,J=6.0Hz,2H),2.18(s,3H),1.63-1.54(m,2H),1.44-1.37(m,2H).

[1105] Preparation of the comparative control compound (compound A)

[1106]

[1107] Synthetic route

[1108]

[1109] Step 1: Synthesis of compound 116-b

[1110] The procedure was the same as for the synthesis of compound 1-d, except that 1-b was replaced with 116-a (3 g, 16.56 mmol) and 1-c was replaced with 4-b (3.2 g, 23.18 mmol), yielding 116-b (2 g, 7.37 mmol). MS m / z (ESI): 272.28 [M+H] + .

[1111] Step 2: Synthesis of compound 116-c

[1112] The procedure was the same as for the synthesis of compound 11-b, except that 7-b was replaced with 116-b (500 mg, 1.84 mmol) to obtain 116-c (650 mg, 1.75 mmol). MS m / z (ESI): 372.08 [M+H] + .

[1113] Step 3: Synthesis of compound 116-d

[1114] The procedure was the same as for the synthesis of compound 11-c, except that 11-b was replaced with 116-c (500 mg, 1.84 mmol) to obtain 116-d (230 mg, 0.67 mmol). MS m / z (ESI): 344.25 [M+H] + .

[1115] Step 4: Synthesis of Compound A

[1116] The procedure was the same as for the synthesis of compound 9, except that 9-d was replaced with 116-d (230 mg, 0.67 mmol) and 9-e was replaced with 2-a (119.8 mg, 0.80 mmol), yielding a yellow solid compound A (90 mg, 0.21 mmol). MS m / z (ESI): 439.11 [M+H] + .

[1117] 1 H NMR (600MHz, DMSO-d6) δ10.54(s,1H),9.35(d,J=8.8Hz,1H),8.21(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.9,2.7 Hz,1H),7.54(t,J=9.1Hz,1H),4.71(h,J=7.5Hz,1H),3.60(s,3H),2.41(s,3H),2.24(s,3H),1.32(d,J=7.0Hz,3H).

[1118] Example 116: In vitro anti-HBV activity assay of HepG2.2.15 cells

[1119] 1. Compound Dilution: Dilution method ① Compound 2-47 Dilution method: First, use DMSO to serially dilute the 20μM compound stock solution 10 times to obtain the 2μM compound. Then, use culture medium to dilute the 20μM and 2μM compounds 200 times to the final concentrations of 100nM and 10nM, respectively. Dilution method for compounds 48-104 and 110-111: First, use DMSO to serially dilute the 20μM compound stock solution 10 times to obtain the 2μM and 0.2μM compounds. Then, use culture medium to dilute the 2μM and 0.2μM compounds 200 times to the final concentrations of 10nM and 1nM, respectively. Dilution method ②, dilution method for compounds 2 and 7: First, the 20 μM stock solution of the compounds was serially diluted 3-fold to 8 concentration points using DMSO to obtain the compounds at serially diluted levels of 20 μM, 6.67 μM, 2.22 μM, 0.741 μM, 0.247 μM, 0.0823 μM, 0.0274 μM and 0.00914 μM. Then, the serially diluted compounds were further diluted 200-fold using culture medium to the final concentrations of 100 nM, 33.3 nM, 11.1 nM, 3.70 nM, 1.23 nM, 0.412 nM, 0.137 nM and 0.0457 nM.

[1120] 2. Experimental Procedure: On the first day, HepG2.2.15 cells (Wuhan Institute of Virology, Chinese Academy of Sciences) (6×10⁻⁶) were... 4 Cells (per well) were seeded into 96-well plates and incubated overnight at 37°C with 5% CO2. Wells containing only cell culture medium and no cells were used as a culture medium control. On the second day, culture media containing different final concentrations of the compound obtained in step 1 were added to the cell culture plates. For dilution method ①, each concentration was tested in triplicate; for dilution method ②, each concentration was tested in duplicate. The final concentration of DMSO in the cell culture medium was 0.5%, and the final volume in each well was 200 μl. Wells containing only 0.5% DMSO without the compound were used as a DMSO control. On the fifth day, the compound-treated wells and control wells were replaced with fresh culture medium prepared using the same methods described above. On the eighth day, the cell supernatant from the culture wells was collected, and a portion of the sample was used to detect the HBV DNA content. A plasmid containing the full-length D-type HBV DNA sequence was used as a standard for qPCR, with a standard range of 10. 7 -10 1 The HBV DNA content in all samples was determined by qPCR using copies / μl. After collecting the supernatant, Cell Titer-Glo reagent was added to the cell culture wells and incubated at room temperature for 10 minutes. Then, the chemiluminescence values ​​in all wells were read using a microplate reader to calculate cell proliferation activity.

[1121] 3. Data Analysis: Calculate the inhibition percentage using the following formula:

[1122] HBV DNA inhibition rate % = (1 - DNA copy number in the compound sample / DNA copy number in the DMSO control)

[1123] (DNA copy number) × 100%.

[1124] Cell Viability% = (Crystal luminescence value in compound sample – Crystal luminescence value in culture medium control) /

[1125] (luminescence value of DMSO control – luminescence value of culture medium control) × 100%.

[1126] The compound was tested according to dilution method ①, and its anti-HBV replication activity EC was obtained based on the HBV DNA inhibition rate (%). 50 Scope; For compounds detected according to dilution method ②, the HBV DNA inhibition rate (%) and compound concentration were fitted using a four-parameter method [log(agonist) vs. response--variable slope] with GraphPad Prism software to obtain the EC50 of the compound's anti-HBV replication activity. 50 Accurate value.

[1127] Using the above experimental methods, the anti-HBV activity and corresponding cell proliferation inhibition activity of some compounds of the present invention are shown in Table 1 below.

[1128] Table 1 HepG2.2.15 HBV DNA inhibition

[1129]

[1130]

[1131]

[1132] Among them, the C2C values ​​of the compounds obtained in Table 1 50 When the range is specified, the dilution method for the compound is method ①; the EC values ​​of the compound are obtained. 50 When calculating the dilution range, except for compounds 2 and 7, the dilution method for the other compounds was method ①, and the dilution method for compounds 2 and 7 was method ②. The EC values ​​for compounds 2 and 7 were... 50 The range is obtained by calculating EC 50 The accurate value is obtained by summarizing.

[1133] As shown in Table 1, the compounds of the present invention have excellent anti-HBV activity; at the measured concentrations, they did not inhibit the viability of hepg2.2.15 cells.

[1134] Example 117: Human Liver Microsomal Stability Test (MMS)

[1135] The human liver microsomes (BIOIVT) were used in the experiment.

[1136] Reagent preparation:

[1137] PBS: 0.1M KH2PO4 and K2HPO4 buffer, pH 7.4.

[1138] MgCl2: Weigh a certain amount of MgCl2 and prepare a 16mM MgCl2 solution using PBS.

[1139] NADPH: Weigh a certain amount of NADPH and use 16mM MgCl2 solution to prepare NADPH to 4mM. The final incubation concentration is 1mM.

[1140] Compounds: The test compounds were prepared to a concentration of 4 μM using PBS, and the final incubation concentration was 1 μM.

[1141] Liver microsomes: Liver microsomes were diluted to 1 mg / mL with PBS, and the final incubation concentration was 0.5 mg / mL.

[1142] Experimental steps:

[1143] Add the test compound to a test tube, followed by the prepared NADPH, and mix thoroughly. Incubate at 37°C and 220 rpm for 5 minutes, then add liver microsomes to initiate the reaction.

[1144] Parallel experimental groups were set up. At 0 min, 5 min, 15 min, 30 min, and 60 min, a certain volume of ice-cold acetonitrile solution containing the internal standard tolbutamide was added to precipitate the protein. The mixture was vortexed for 5 min, followed by centrifugation at 4000 rpm for 10 min. The supernatant was collected into a 96-well plate and analyzed by LC-MS / MS (Shimadzu LC-30A, AB API4500).

[1145] The concentration (peak area ratio) of the compounds in the examples was determined by LC-MS / MS. The rate constant was obtained by plotting "Ln (residual amount of compound %)" against "incubation time" in Excel, thereby calculating the drug's half-life and intrinsic clearance rate, providing a basis for predicting in vivo clearance rate.

[1146] Data Analysis:

[1147] CL int =(0.693 / t) 1 / 2 Microsomes) × [Incubation liquid volume (ml) / Microsome protein content (mg)] × [micro...

[1148] [Mitochondrial protein mass (mg) / liver mass (g)] × [liver mass (g) / body weight (kg)] [8]

[1149] [8] CL H =CL int ×f u ×Q h / (CL int ×f u +Q h )

[1150] In the formula

[1151] CL int --Inherent clearance rate (ml / min / kg)

[1152] CL H --Liver clearance rate (ml / min / kg)

[1153] f u --Plasma protein binding rate is 1

[1154] Q h --Hepatic blood flow

[1155] Experimental results: Control compound B (structural formula: The half-life and liver clearance of the compound of the present invention in human liver microsomal stability assay (MMS) are shown in Table 2 below, which describes the preparation method of compound 19 as described in patent document WO2015011281A1.

[1156] Table 2: Human Liver Microsomal Stability Test (MMS)

[1157]

[1158]

[1159] As shown in Table 2, the compounds of the present invention all have a longer half-life and a longer duration of action in vivo, which is beneficial to improving drug efficacy.

[1160] Example 118: Mouse Tissue Distribution Experiment

[1161] Experimental materials and methods:

[1162] The experimental animals were female BALB / c mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

[1163] Female BALB / c mice were orally administered the drug (30 mg / kg) via gavage. Plasma, brain, liver, heart, and kidney samples were collected at different time points at 0.5, 1, 3, 5, and 8 h post-administration. For plasma, 60 μL of whole blood from the fundus venous plexus was collected and centrifuged at 4000 rpm for 10 min. The peritoneal cavity was opened, the heart was perfused with physiological saline, and brain, liver, heart, and kidney tissues were collected. After wiping away moisture with filter paper, the tissues were weighed and mixed with physiological saline at a 1:2 ratio. The mixture was homogenized and placed into EP tubes.

[1164] Sample analysis:

[1165] Take 10 μL of mouse plasma and each tissue sample, add 290 μL of acetonitrile solution containing the internal standard tolbutamide to precipitate proteins, vortex for 10 min, then centrifuge at 4000 rpm for 10 min, and collect the supernatant in a 96-well plate. Analyze using LC-MS / MS (Shimadzu LC-30A, AB API 4500).

[1166] The drug concentrations in plasma and tissues of mice at different time points after gavage administration of control compound A and example compound were determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compound in mice and evaluate its pharmacokinetic characteristics.

[1167] Experimental results: The distribution data of control compound A, compound 4, compound 7 and compound 16 of the present invention in mouse tissues are shown in Tables 3-6 below.

[1168] Table 3: Data on the distribution of control compound A in mouse tissues:

[1169]

[1170] Table 4: Data on the distribution of compound 4 of the present invention in mouse tissues:

[1171]

[1172] Table 5: Data on the distribution of compound 7 of the present invention in mouse tissues:

[1173]

[1174]

[1175] Table 6: Data on the distribution of compound 16 of the present invention in mouse tissues

[1176]

[1177] As shown in Tables 3-6, compared with control compound A, the exposure levels of compounds 4, 7 and 16 of the present invention in the liver, the target organ, remained at a high and stable level after administration from 0 to 8 hours, which were 13.3 times, 12.89 times and 71.8 times that of control compound A, respectively. This indicates that the compounds of the present invention can exert their effects in the target organ better.

[1178] Example 119: Solubility Test

[1179] Experimental Methods: The compound of the present invention was dissolved in DMSO and serially diluted to prepare compound solutions of 500 3.2 μg / ml, 250 1.6 μg / ml, 1250.8 μg / ml, 625.4 μg / ml, 312.7 μg / ml, and 156.4 μg / ml. Physiological medium buffer solutions of pH 2.0 hydrochloric acid and pH 6.8 phosphate buffer were then prepared. The compound solutions of each concentration were diluted with the above physiological medium buffer solutions to prepare solutions of concentrations of 250.2 μg / ml, 125.1 μg / ml, 62.5 μg / ml, 31.3 μg / ml, 15.6 μg / ml, and 7.8 μg / ml, respectively, and then shaken well. The absorbance was measured at 633 nm using an ELISA reader (manufacturer: TECAN, model: Spark). The OD values ​​of each concentration solution were compared with the OD value of the blank control physiological medium buffer to determine the solubility range of the compound of the present invention.

[1180] Experimental results: The solubility of the compound of the present invention in hydrochloric acid solution at pH 2.0 is 125.1-250.2 ug / ml, and the solubility in phosphate buffer solution at pH 6.8 is 15.6-31.3 ug / ml, indicating that the solubility of the compound of the present invention has a significant advantage, which is beneficial to improving the efficacy of the drug.

[1181] Industrial applicability

[1182] The compounds of this invention have excellent anti-HBV activity and can be used as drugs for the treatment or prevention of diseases related to this activity.

[1183] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

[1184] References:

[1185] [1]Villain P,Gonzalez P,Almonte M,et al.European Code against Cancer4th Edition:Infections and Cancer[J].Cancer Epidemiology,2015.

[1186] [2]Samuel,E C.Antiviral actions of interferons[Table of Contents][J].Clinical Microbiology Reviews,2001,14(4):778-809.

[1187] [3]A R G G,B B G,C C L L,et al.Chronic hepatitis B:Virology,naturalhistory,current management and a glimpse at future opportunities-ScienceDirect[J].Antiviral Research,2015,121:47-58.

[1188] [4]Elias S,Smith C I,Ghany M G.Hepatitis B:Current Status of Therapyand Future Therapies[J].Gastroenterology clinics of North America,2021.

[1189] [5]Berke,Martin J,Dehertogh,et al.Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes withhepatitis B virus.

[1190] [6]Berke J M,Dehertogh P,Vergauwen K,et al.Capsid Assembly ModulatorsHave a Dual Mechanism of Action in Primary Human Hepatocytes Infected withHepatitis B Virus[J].Antimicrob Agents Chemother,2017:AAC.00560-17.

[1191] [7]Angela,M,Lam,et al.Preclinical Characterization of NVR 3-778,aFirst-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus.[J].Antimicrobial Agents & Chemotherapy,2018.

[1192] [8]Davies B,Morris T.Physiological parameters in laboratory animalsand humans.Pharm Res.1993;10:1093-5.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in, R1 is selected from methyl, -F, -Cl, -Br; R2 is selected from methyl; R3 is selected from substituted or unsubstituted phenyl groups; the substituents of the phenyl group are selected from -F, -Cl, -Br, -CN; R4 is selected from C 1-8 Alkyl, substituted C 1-6 Alkyl; the C 1-6 The alkyl substituents are selected from halogens, C 1-4 Alkoxy, C 2-4 Alkyne group.

2. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in, R1 is selected from methyl, -F, -Cl, -Br; R2 is selected from methyl; R3 is selected from substituted or unsubstituted phenyl groups; the substituents of the phenyl group are selected from -F, -Cl, -Br, -CN; R4 is selected from C 1-8 Alkyl, substituted C 1-6 Alkyl; the C 1-6 The alkyl substituents are selected from -F, -Cl, -Br, methoxy, and ethynyl.

3. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in, R1 is selected from methyl, -F, -Cl, -Br; R2 is selected from methyl; R3 is selected from substituted or unsubstituted phenyl groups; the substituents of the phenyl group are selected from -F, -Cl, -Br, -CN; R4 is selected from tert-butyl, 4. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in, R1 is selected from methyl, -F, -Cl, -Br; R2 is selected from methyl; R3 is selected from substituted or unsubstituted phenyl groups; the substituents of the phenyl group are selected from -F, -Cl, -Br, -CN; R4 is selected from tert-butyl, 5. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in, R1 is selected from methyl, -F, -Cl, -Br; R2 is selected from methyl; R3 is selected from substituted or unsubstituted phenyl groups; the substituents of the phenyl group are selected from -F, -Cl, -Br, -CN; R4 is selected from tert-butyl, 6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: R1 is selected from methyl.

7. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: R3 is selected from 8. The compound according to claim 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: R3 is selected from 9. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: It has the structure shown in equation V: The definitions of R1, R2, and R3 are as described in claim 1.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: Selected from the following structures: The definitions of R2 and R3 are as described in claim 1.

11. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: Selected from the following structures: The definitions of R2 and R3 are as described in claim 1.

12. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: Selected from the following structures: The definitions of R2 and R3 are as described in claim 1.

13. A pyrrolamide compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: Selected from the following compounds:

14. A pharmaceutical composition comprising the compound of any one of claims 1-13, a pharmaceutically acceptable salt thereof, a stereoisomer or tautomer thereof, and a pharmaceutically acceptable auxiliary ingredient.

15. Use of the compound of any one of claims 1-13, its pharmaceutically acceptable salt, stereoisomer or tautomer, or the pharmaceutical composition of claim 14 in the preparation of a medicament for treating HBV infection.

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