TW202400558A - Pyrrolamide compounds and preparation method and use thereof - Google Patents

Abstract

The present invention relates to a pyrrolamide compound, a preparation method thereof and use thereof. The structure of the compound is shown in formula (I). The compound is a type of new anti-HBV compound. The present invention also relates to a pharmaceutical composition including the compound as an active ingredient, which can be used for treating and/or preventing HBV infection and has important application value.

Description

Pyrrolamide compounds and their preparation methods and uses

The invention belongs to the field of medicine, and specifically relates to a pyrrolidamide compound used to treat HBV infection and its preparation method and use.

Hepatitis B virus (HBV) can cause viral hepatitis B and remains one of the most concerning viruses in the world. Currently, more than 250 million people worldwide carry hepatitis B virus, and these patients are at increased risk of major liver diseases including cirrhosis, permanent scarring of the liver, liver failure, and cancer. The World Health Organization estimates that more than 780,000 people die from hepatitis B disease each year. According to data from the Hepatitis B Foundation, hepatitis B virus accounts for 80% of the factors that induce liver cancer, and the five-year survival rate of liver cancer patients is usually only 15%.

Despite the existence of effective vaccines, vaccine coverage remains unsatisfactory in HBV endemic areas ^[1] . Currently, there are two main classes of drugs approved for the treatment of chronic hepatitis B. One type is interferon (IFN-α) and its pegylated form (Peg-IFN-α). IFN-α is an immunomodulator that can induce interferon-stimulated genes in a non-specific manner. , ISGs) expression. This gene encodes a constitutive or secreted protein with direct or indirect antiviral properties, thereby promoting the differentiation or activation of immune cells ^[2] . After 48 weeks of subcutaneous injection of IFN-α, the effective rate in HBV patients was only 25% ^[3] . In addition to the low response rate, IFN-α also has other shortcomings, such as the need for injection administration, severe flu-like symptoms and other adverse reactions, and contraindications for patients with compensated cirrhosis, severe hepatitis, and autoimmune and psychological diseases. Another type of approved drugs are nucleoside analogs (NAs). There are currently 5 approved NAs including lamivudine (LMV), Telbivudine (Ldt), and adefovir dipivoxil (ADV), tenofovir (TFV), entecavir (ETV). NAs lead to the reduction of virions by directly inhibiting the activity of HBV polymerase, thus interrupting the circulation of nucleocapsids to the nucleus of infected cells and theoretically reducing the expression of cccDNA. However, NAs treatment cannot inhibit the de novo synthesis of cccDNA in newly infected cells, which indicates that residual virus particles during antiviral treatment will lead to the infection of new cells and the reconstruction of the cccDNA library. Once the patient stops taking the drug on his own, it may cause virological rebound. Therefore, chronic hepatitis B virus infection rarely achieves functional cure, and most patients need to take drugs for life. However, long-term use of NAs drugs can easily cause the virus to mutate and develop drug resistance.

Based on the shortcomings of current therapies, some drugs targeting the HBV replication cycle or enhancing the body's immune response are being developed and have entered the clinical research stage. Among them, the core protein in the HBV replication process is crucial for the packaging and reverse transcription of HBV pgRNA. The molecules developed for this protein are called core protein allosteric modulators or capsid assembly modulators (CpAMs). CpAMs can be divided into two categories according to their mechanism of action: Class I CpAMs, represented by heteroaryldihydropyrimidines (HAP), whose mechanism of action is to enhance the kinetics of nucleocapsid formation, leading to misassembly of nucleocapsids; Class II CpAMs, represented by phenylacrylamides (PPAs) and sulfabenzamides (SBAs) structural types, their mechanism of action is to accelerate nucleocapsid assembly and form normal morphology but lack viral pgRNA and HBV polymerase packaging nucleocapsid inside ^[4] .

Antiviral studies on nucleocapsid inhibitors BAY41-4109 (HAP) and JNJ-632 (SBA) with different mechanisms were conducted in human primary hepatocytes and found that CpAMs can not only inhibit HBV replication, but also inhibit HBV RNA transcription. and antigen production, suggesting that CpAMs have a dual mechanism of action to inhibit the early and late stages of the virus ^[5-6] . NVR3-778 (SBA), as an early-developed CpAMs molecule, shows strong anti-HBV activity, with an EC ₅₀ of 0.4 μM in HepG2.2.15 cells. Similarly, effective anti-HBV activity was also shown in a humanized liver mouse model of HBV infection ^[7] . With the advancement of science and technology, current drug developers have designed and screened out molecular structures with in vitro anti-HBV activity up to nM level, such as GLP-26, RG7907, etc.

Most of the current anti-HBV drugs show good anti-HBV activity in vitro. However, after entering the clinic, some drugs failed in clinical trials due to low efficacy and some adverse reactions such as increased ALT and recurrence after drug withdrawal. Therefore, although there are currently many drugs and methods for treating HBV, molecules with new structural types and new mechanisms of action for curing hepatitis B are still urgently needed in the field of HBV treatment.

The technical problem to be solved by the present invention is to provide a compound with excellent anti-HBV effect and a completely new structure.

In order to solve the above technical problems, the present invention provides a compound represented by formula (I), or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer: [Chemical formula 1] (I) Wherein, R ₁ 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, halogen, or nitrile group; R ₂ 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, or C _2-8 alkynyl; R ₃ is selected from substituted or unsubstituted C _6-10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl ; The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the C _6-10 aryl group is selected from halogen, C _1-8 alkyl, C _1-8 Haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the 5-10 membered heteroaryl is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy group, or -CN; R ₄ is selected from substituted or unsubstituted C _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 alkynyl, , ,or ; The substituent of the C _1-10 alkyl group is selected from -H, deuterium, halogen, -OH, -COOH, -C(O)NR ^a R ^b , substituted or unsubstituted 5-6 membered heteroaryl, C _3-8 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, C _1-8 alkoxy, or C _2-8 alkynyl; the 5-6 membered heteroaryl contains 1 to 3 Heteroatom selected from N, O or S; the 5-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; -CH on the 5-6 membered heterocycloalkyl ring ₂ - optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the substituent of the 5-6 membered heteroaryl is selected from halogen, C _{1- 8} alkyl, -NH ₂ , -OH, or -CF ₃ ; the substituent of the 5-6 membered heterocycloalkyl is selected from -OH, or C _1-8 alkyl; R ^a and R ^b are each independently selected From -H, or C _1-4 alkyl; -CH ₂ - on the C _3-14 cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S( =O) ₂ -substitution; the substituent of the C _3-14 cycloalkyl group is selected from -H, deuterium, C _1-8 hydroxyalkyl group, -C(O)NH ₂ , -OH, -COOH, halogen, substitution Or unsubstituted 5-6 membered heteroaryl, -CF ₃ , C _1-8 alkyl, -NH ₂ , C _1-8 alkoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or C _2-8 alkynyl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _{1- 8} haloalkyl, or C _1-8 alkyl; -CH ₂ - on the 4-14-membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S (=O) ₂ - substitution; the 4-14-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the 4-14-membered heterocycloalkyl group is selected from C _{1- 8-} hydroxyalkyl, -CF ₃ , -OH, -COOH, C _1-8 alkyl, C _1-8 carbonyl, -S(O) ₂ CH ₃ , 4-6 membered heterocycloalkyl, 5-6 membered Heteroaryl, C _2-8 alkynyl, or halogen-substituted phenyl; the 4-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl The 5-10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 5-10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 5-10-membered heteroaryl group The substituent is selected from C _1-8 alkyl, halogen, -COOH, or -CF ₃ ; the substituent of the C _6-10 aryl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, - COOH, or -B(OH) ₂ ; R ₅ is selected from -H, deuterium, or -OH; R ₆ is selected from -H, deuterium, C _1-8 alkyl, or -NH ₂ ; m is selected from 0 or 1 ; Ring A is selected from 5-6 membered heteroaryl, or phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O or S.

In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₁ is selected from -H, C _1-6 alkane base, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, halogen, or nitrile group.

In one embodiment, R ₁ 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 base, or halogen.

In one embodiment, R ₁ is selected from C _1-4 alkyl, cyclopropyl, C _1-4 deuterated alkyl, C _1-4 alkoxy, C _1-4 deuterated alkoxy, or halogen .

In one embodiment, _R1 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, Propoxy, butoxy, pentoxy, hexyloxy, -F, -Cl, -Br, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, Deuterated hexyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated butoxy, deuterated pentyloxy, or deuterated hexyloxy.

In one embodiment, R1 is selected from methyl, methoxy, _-CD3 , -O- _CD3 , -F, -Cl, or -Br.

In one embodiment, _R1 is selected from methyl.

In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₂ is selected from -H, C _1-6 alkane base, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _1-6 deuterated alkyl, C _1-6 hydroxyalkyl, or C _2-6 alkynyl.

In one embodiment, R ₂ is selected from -H, C _1-6 alkyl, C _3-4 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, or .

In one embodiment, _R2 is selected from -H, C _1-4 alkyl, C _1-4 deuterated alkyl, cyclopropyl, or C _1-4 haloalkyl.

In one embodiment, R _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.

In _one embodiment, _R2 is selected from -H, methyl, ethyl, _-CHF2 , _-CF3 , _-CH2CH2F , or _-CD3 .

In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₃ is selected from substituted or unsubstituted phenyl, Substituted or unsubstituted pyridyl, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 8} alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN.

In one embodiment, _R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN.

In one embodiment, _R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or ; The substituent of the phenyl group is selected from -F, -Cl, -Br, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, or -CN; the substituent of the pyridyl group Selected from -F, -Cl, -Br, or C _1-4 alkyl.

In one embodiment, _R3 is selected from , , , , , , , , , , , , , , , , ,or .

In one embodiment, _R3 is selected from , , , , , , , , , , , , , , ,or .

In one embodiment, _R3 is selected from , , , , , , , , , , , ,or .

In one embodiment, _R3 is selected from , ,or .

In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₄ is selected from substituted or unsubstituted C _{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 alkynyl, , ,or ; The substituent of the C _1-8 alkyl group is selected from -H, deuterium, halogen, -OH, -COOH, -C(O)NR ^a R ^b , substituted or unsubstituted 5-6 membered heteroaryl, C _3-6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, C _1-6 alkoxy, or C _2-6 alkynyl; the 5-6 membered heteroaryl contains 1 to 3 Heteroatom selected from N, O or S; the 5-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; -CH on the 5-6 membered heterocycloalkyl ring ₂ - optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the substituent of the 5-6 membered heteroaryl is selected from halogen, C _{1- 6} alkyl, -NH ₂ , -OH, or -CF ₃ ; the substituent of the 5-6 membered heterocycloalkyl is selected from -OH, or C _1-6 alkyl; R ^a and R ^b are each independently selected From -H, or C _1-4 alkyl; -CH ₂ - on the C _3-12 cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S( =O) ₂ -substitution; the substituent of the C _3-12 cycloalkyl group is selected from -H, deuterium, C _1-6 hydroxyalkyl group, -C(O)NH ₂ , -OH, -COOH, halogen, substitution Or unsubstituted 5-6 membered heteroaryl, -CF ₃ , C _1-6 alkyl, -NH ₂ , C _1-6 alkoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or C _2-6 alkynyl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _{1- 6} haloalkyl, or C _1-6 alkyl; -CH ₂ - on the 4-10 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S (=O) ₂ -replacement; the 4-10-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the 4-10-membered heterocycloalkyl group is selected from C _{1- 6-} hydroxyalkyl, -CF ₃ , -OH, -COOH, C _1-6 alkyl, C _1-6 carbonyl, -S(O) ₂ CH ₃ , 4-6 membered heterocycloalkyl, 5-6 membered Heteroaryl, C _2-6 alkynyl, or halogen-substituted phenyl; the 4-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl The 5-8-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S; the 5-8-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S; the 5-8-membered heteroaryl group The substituent is selected from C _1-6 alkyl, halogen, -COOH, or -CF ₃ ; the substituent of the C _6-9 aryl group is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, - COOH, or -B(OH) ₂ .

In one embodiment, R ₄ 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 heterocycle Alkyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C _6-9 aryl, C _2-6 alkynyl, , , ,or ; The substituent of the C _1-6 alkyl group is selected from -H, deuterium, halogen, -OH, -C(O)NH ₂ , substituted or unsubstituted 5-6 membered heteroaryl, C _3-6 cycloalkyl base, substituted or unsubstituted 5-6 membered heterocycloalkyl, C _1-4 alkoxy, or C _2-4 alkynyl; the 5-6 membered heteroaryl contains 1 to 3 selected from N, O Or a heteroatom of S; the 5-6-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; -CH ₂ - on the 5-6-membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -replacement; the substituent of the 5-6 membered heteroaryl is selected from halogen, C _1-4 alkyl, - NH ₂ , -OH, or -CF ₃ ; the substituent of the 5-6 membered heterocycloalkyl group is selected from -OH, or C _1-4 alkyl group; -CH ₂ on the C _3-10 cycloalkyl ring - optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the substituent of the C _3-10 cycloalkyl group is selected from -H, deuterium, C _1-4 hydroxyalkyl, -C(O)NH ₂ , -OH, halogen, substituted or unsubstituted 5-6 membered heteroaryl, -CF ₃ , C _1-4 alkyl, -NH ₂ , C _{1 -4} alkoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or C _2-4 alkynyl; the 5-6 membered heteroaryl contains 1 to 4 selected from N, O or Heteroatom of S; the substituent of the 5-6 membered heteroaryl is selected from C _1-4 haloalkyl or C _1-4 alkyl; -CH ₂ - on the 4-10 membered heterocycloalkyl ring is any Selected to be replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the 4-10-membered heterocycloalkyl group contains 1 to 3 selected from N, O or S heteroatoms; the substituents of the 4-10 membered heterocycloalkyl are selected from C _1-4 hydroxyalkyl, -CF ₃ , -OH, C _1-4 alkyl, C _1-4 carbonyl, -S(O ) ₂ CH ₃ , 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C _2-4 alkynyl, or halogen-substituted phenyl; the 4-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from Heteroatom of N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _1-4 alkyl, halogen, or -CF ₃ ; the substituent of the C _6-9 aryl group is selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, or -B(OH) ₂ .

In one embodiment, R ₄ is selected from C _1-8 alkyl, substituted C _1-6 alkyl, , , , , , , , , , , , substituted C _3-7 cycloalkyl, substituted 4-6 membered heterocycloalkyl, , , , , , , , , , , , , substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted phenyl, C _2-4 alkynyl, , , ,or ; The substituent of the C _1-6 alkyl group is selected from -H, deuterium, -F, -Cl, -Br, -OH, -C(O)NH ₂ , cyclopropyl, methoxy, ethynyl, , , , , , , , , , , , , , , ,or ; The substituent of the C _3-7 cycloalkyl group is selected from -H, deuterium, hydroxymethyl, , -C(O)NH ₂ , -OH, -F, -Cl, -Br, , , , , -CF ₃ , methyl, ethyl, -NH ₂ , methoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or ethynyl; the 4-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; the substituents of the 4-6 membered heterocycloalkyl are selected from C _1-4 hydroxyalkyl, -CF ₃ , -OH, C _1-4 alkyl , C _1-4 carbonyl group, -S(O) ₂ CH ₃ , , , pyridyl, pyrimidinyl, thienyl, pyridyl, pyridyl, C _2-4 alkynyl, or chlorine-substituted phenyl; the 5-6 membered heteroaryl is selected from pyridyl, thiazolyl, isotriyl Azolyl, pyrazolyl; the substituent of the 5-6 membered heteroaryl is selected from C _1-4 alkyl, halogen, or -CF ₃ ; the substituent of the phenyl is selected from halogen, C _1-4 alkyl , C _1-4 haloalkyl, or -B(OH) ₂ .

In one embodiment, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In one embodiment, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In one embodiment, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In one embodiment, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In one embodiment, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , ,or .

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by Formula V: [Chemical Formula 2] Formula V Among them, the definitions of R ₁ , R ₂ and R ₃ refer to the aforementioned definitions.

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by Formula Va: [Chemical Formula 3] Formula Va Where, the definitions of R ₂ and R ₃ refer to the aforementioned definitions.

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula Vaa: [Chemical Formula 4] Formula Vaa Where, the definitions of R ₂ and R ₃ refer to the aforementioned definitions.

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula Vab: [Chemical Formula 5] Formula Vab Among them, the definitions of R ₂ and R ₃ refer to the aforementioned definitions.

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure shown in Formula VI: [Chemical Formula 6] Formula VI Where, the definition of R ₄ refers to the previous definition.

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure shown in Formula VII: [Chemical Formula 7] Formula VII Where, the definition of R ₄ refers to the previous definition.

In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure shown in Formula VIII: [Chemical Formula 8] Formula VIII Where, the definition of R ₄ refers to the previous definition.

In one embodiment, the present invention provides a compound represented by formula (1), or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer: [chemical formula 9] Formula (1) wherein R ₁₁ 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 group, C _1-8 deuterated alkoxy group, halogen, or nitrile group; R ₁₂ is selected from -H, C _1-8 alkyl group, C _3-8 cycloalkyl group, C _1-8 haloalkyl group, C _{1- 8} deuterated alkyl, C _1-8 hydroxyalkyl, or C _2-8 alkynyl; R ₁₃ is selected from C _6-10 aryl that is unsubstituted or substituted by one or more identical or different substituents, or a 5-10-membered heteroaryl group that is unsubstituted or substituted by one or more identical or different substituents; the 5-10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; The substituent of the C _6-10 aryl group is selected from halogen, C _1-8 alkyl group, C _1-8 haloalkyl group, C _1-8 haloalkoxy group, or -CN; the substitution of the 5-10 membered heteroaryl group The group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; R ₁₄ is selected from C _2-8 alkynyl, unsubstituted or substituted by 1 or more C _6-10 aryl group substituted by the same or different substituents, C _5-12 bridged cycloalkyl group unsubstituted or substituted by 1 or more same or different substituents, unsubstituted or substituted by 1 or more 5-10 membered heteroaryl groups substituted with the same or different substituents, or ; The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the C _6-10 aryl group is selected from halogen, -B(OH) ₂ , C _1-8 Alkyl, C _1-8 haloalkyl, or -COOH; the substituent of the 5-10 membered heteroaryl is selected from halogen, C _1-8 alkyl, -COOH, -C(O)NR ^e R ^f , or C _1-8 haloalkyl; the substituent of the C _5-12 bridged cycloalkyl is selected from -OH; R ₁₅ and R ₁₆ are each independently selected from -H, C _1-8 alkyl, C _1-8 haloalkyl , C _1-8 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a C _3-12 cycloalkyl group that is unsubstituted or substituted by one or more identical or different substituents, or 3-10 membered heterocycloalkyl that is unsubstituted or substituted by 1 or more identical or different substituents; the 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S ; The substituent of the C _3-12 cycloalkyl group is selected from deuterium, C _1-8 hydroxyalkyl group, C _1-8 haloalkyl group, C _1-8 alkyl group, -C(O)NR ^e R ^f , -NR ^e R ^f , -COOR ^e , halogen, -OH, C _1-8 alkoxy group; the substituent of the 3-10 membered heterocycloalkyl group is selected from C _1-8 hydroxyalkyl group, C _1-8 haloalkyl group, -OH, -COOR ^e , -C(O)NR ^e R ^f , C _1-8 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is 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, C _1-8 hydroxyalkyl, C _1-8 alkoxy C _1-8 alkyl, C _3-8 cycloalkyl, unsubstituted or 1 or more the same or different A 5-6 membered heteroaryl group substituted with a substituent, or a 4-6 membered heterocycloalkyl group that is unsubstituted or substituted by one or more identical or different substituents; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 4-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; the substituents of the 5-6 membered heteroaryl group Selected from C _1-8 alkyl, halogen, -NR ^e R ^f , -OH, C _1-8 haloalkyl, or C _1-8 deuterated alkyl; the substituent of the 4-6 membered heterocycloalkyl is selected from From C _1-8 alkyl, -OH, or -S(O) ₂ R ^g ; ^Re , R ^f , and R ^g are each independently selected from -H, or C _1-4 alkyl.

In some embodiments, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₁₁ is selected from -H, C _1-6 alkane base, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, halogen, or nitrile group.

In some embodiments, R ₁₁ 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 base, or halogen.

In some embodiments, R ₁₁ is selected from C _1-4 alkyl, cyclopropyl, C _1-4 deuterated alkyl, C _1-4 alkoxy, C _1-4 deuterated alkoxy, or halo .

In some embodiments, _R11 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, Propoxy, butoxy, pentoxy, hexyloxy, -F, -Cl, -Br, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, Deuterated hexyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated butoxy, deuterated pentyloxy, or deuterated hexyloxy.

In some embodiments, R ₁₁ is selected from methyl, methoxy, -CD ₃ , -O-CD ₃ , -F, -Cl, -Br, or -CF ₃ .

In some embodiments, R ₁₁ is selected from methyl, -CD ₃ , -F, -Cl, -Br, or -CF ₃ .

In some embodiments, R ₁₁ is selected from methyl.

In some embodiments, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₁₂ is selected from -H, C _1-6 alkane base, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _1-6 deuterated alkyl, C _1-6 hydroxyalkyl, or C ₂ - ₆ alkynyl.

In some embodiments, R ₁₂ is selected from -H, C _1-6 alkyl, C _3-4 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, or .

In some embodiments, R ₁₂ 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.

In some embodiments, R ₁₂ is selected from -H, C _1-4 alkyl, C _1-4 deuterated alkyl, cyclopropyl, or C _1-4 haloalkyl.

In some embodiments, R ₁₂ is selected from -H, methyl, ethyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, or -CD ₃ .

In some embodiments, R ₁₂ is selected from -H, methyl, -CHF ₂ , -CF ₃ , or -CD ₃ .

In some embodiments, R ₁₂ is selected from methyl, or -CD ₃ .

In some embodiments, R ₁₂ is selected from methyl.

In some embodiments, in the above compounds, or their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers, R ₁₃ is selected from unsubstituted or substituted by 1 or more phenyl substituted by the same or different substituents, pyridyl unsubstituted or substituted by one or more identical or different substituents, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 8} alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN.

In some embodiments, R ₁₃ is selected from phenyl, unsubstituted or substituted with 1, 2, 3 or 4 the same or different substituents, unsubstituted or substituted with 1, 2, 3 or 4 Pyridyl substituted with the same or different substituents, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN.

In some embodiments, R ₁₃ is selected from phenyl, unsubstituted or substituted with 1, 2 or 3 the same or different substituents, unsubstituted or substituted with 1, 2 or 3 the same or different substituents substituted pyridyl, or ; The substituent of the phenyl group is selected from -F, -Cl, -Br, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, or -CN; the substituent of the pyridyl group Selected from -F, -Cl, -Br, or C _1-4 alkyl.

In some embodiments, R ₁₃ is selected from , , , , , , , , , , , , , , , , , ,or .

In some embodiments, R ₁₃ is selected from , , , , , , , , , , , , , , , ,or .

In some embodiments, R ₁₃ is selected from , , , , , , , , , , , , ,or .

In some embodiments, R ₁₃ is selected from , , , , ,or .

In some embodiments, R ₁₃ is selected from , ,or .

In some embodiments, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R ₁₄ is selected from C _2-6 alkynyl, un Substituted or substituted phenyl with 1 or more identical or different substituents, unsubstituted or substituted with 1 or more identical or different substituents C _5-10 bridged cycloalkyl, unsubstituted or substituted with 1 Pyridyl substituted with one or more identical or different substituents, or ; The substituent of the phenyl group is selected from halogen, -B(OH) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, or -COOH; the substituent of the pyridyl group is selected from halogen, C _1-6 Alkyl, -COOH, -C(O)NR ^e R ^f , or C _1-6 haloalkyl; the substituent of the C _5-10 bridged cycloalkyl is selected from -OH; R ₁₅ and R ₁₆ are each independently selected From -H, C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected are selected from the group consisting of unsubstituted or substituted by one or more A C _3-10 cycloalkyl group substituted with the same or different substituents, or a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted with 1 or more same or different substituents; the 3-8 membered heterocycloalkyl group The cycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; the substituents of the C _3-10 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, or C _1-6 alkoxy; the 3-8 membered heterocycloalkyl The substituent is selected from C _1-6 hydroxyalkyl, C _1-6 haloalkyl, -OH, -COOR ^e , -C(O)NR ^e R ^f , C _1-6 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is 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, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heteroaryl unsubstituted or substituted by 1 or more identical or different substituents, or unsubstituted or substituted by 1 or more identical or different substituents 4-6 membered heterocycloalkyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O or S; the 4-6 membered heterocycloalkyl contains 1 to 2 selected from N , O or S heteroatom; the substituent of the 5-6 membered heteroaryl is selected from C _1-6 alkyl, halogen, -NR ^e R ^f , -OH, C _1-6 haloalkyl, or C _{1- 6} deuterated alkyl; the substituent of the 4-6 membered heterocycloalkyl is selected from C _1-6 alkyl, -OH, or -S(O) ₂ R ^g ; R ^e , R ^f , and R ^g are each independent is selected from -H, or C _1-4 alkyl.

In some embodiments, R ₁₄ is selected from C _2-6 alkynyl, unsubstituted or phenyl substituted with 1 or more the same or different substituents, unsubstituted or substituted with 1 or more the same or different substituents C _5-10 bridged cycloalkyl substituted by substituents, pyridyl unsubstituted or substituted by 1 or more identical or different substituents, or ; The substituent of the phenyl group is selected from halogen or -B(OH) ₂ ; the substituent of the pyridyl group is selected from halogen; the substituent of the C _5-10 bridged cycloalkyl group is selected from -OH; R ₁₅ , R ₁₆ is each independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a group selected from unsubstituted or C _3-10 cycloalkyl substituted by 1 or more identical or different substituents, or 3-8 membered heterocycloalkyl unsubstituted or substituted by 1 or more identical or different substituents; the The 3-8-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; the substituent of the C _3-10 cycloalkyl group is selected from halogen, -OH, or C _1-6 alkoxy group ; The substituent of the 3-8-membered heterocycloalkyl is selected from C _1-6 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is selected from -H, -CN, -C(O)NR ^e R ^f , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 Alkyl, C _3-6 cycloalkyl, 5-6 membered heteroaryl unsubstituted or substituted by 1 or more identical or different substituents, or unsubstituted or substituted by 1 or more identical or different substituents 4-6 membered heterocycloalkyl substituted by substituents; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O or S; the 4-6 membered heterocycloalkyl contains 1 to 2 A heteroatom selected from N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 deuterated alkyl; the The substituent of the 4-6 membered heterocycloalkyl group is selected from C _1-6 alkyl, or -OH; R ^e , R ^f , and R ^g are each independently selected from -H, or C _1-4 alkyl.

In some embodiments, R ₁₄ is selected from C _2-4 alkynyl, phenyl unsubstituted or substituted with 1, 2 or 3 the same or different substituents, , , , unsubstituted or pyridyl substituted by 1, 2 or 3 identical or different substituents, or ; The substituent of the phenyl group is selected from halogen, or -B(OH) ₂ ; the substituent of the pyridyl group is selected from halogen; R ₁₅ and R ₁₆ are each independently selected from -H, C _1-4 alkyl, C _1-4 haloalkyl, or C _1-4 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a group selected from unsubstituted or substituted by 1, 2 or 3 identical or different substituents. C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl that is unsubstituted or substituted by 1, 2 or 3 identical or different substituents; the 3-8 membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O or S; the substituent of the C _3-8 cycloalkyl group is selected from halogen, -OH, C _1-4 alkoxy group; the substitution of the 3-8 membered heterocycloalkyl group The group is selected from C _1-4 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is selected from -H, -CN, -C(O)NR ^e R ^f , C _{1 -4} alkyl, C _1-4 haloalkyl, C _2-4 alkynyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl, un 5-6 membered heteroaryl substituted or substituted by 1, 2 or 3 identical or different substituents, or 5- unsubstituted or substituted by 1, 2 or 3 identical or different substituents 6-membered heterocycloalkyl; the 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from N and O; the 5-6-membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N and O Atom; the substituent of the 5-6 membered heteroaryl group is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuterated alkyl; the substituent of the 5-6 membered heterocycloalkyl group Selected from C _1-4 alkyl or -OH; ^Re , R ^f and R ^g are each independently selected from -H or C _1-4 alkyl.

In some embodiments, R ₁₄ is selected from C _2-4 alkynyl, unsubstituted or phenyl substituted with 1 or 2 identical or different substituents, , , , unsubstituted or pyridyl substituted by 1 or 2 identical or different substituents, or ; The substituent of the phenyl group is selected from -F, -Cl, -Br, or -B(OH) ₂ ; the substituent of the pyridyl group is selected from -F, -Cl, or -Br; R ₁₅ and R ₁₆ are each Independently selected from -H, methyl, ethyl, isopropyl, tertiary butyl, -CF ₃ , -CH ₂ F, or hydroxymethyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a selected From cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _4-7 cycloalkyl substituted by 1 or 2 identical or different substituents, unsubstituted or substituted by 1 or 2 identical or different A 4-8-membered heterocycloalkyl group substituted with a substituent; the 4-8-membered heterocycloalkyl group contains 1 heteroatom selected from N, O or S; the substituent of the C _4-7 cycloalkyl group is selected from -F, -Cl, -Br, -OH, methoxy, or ethoxy; the substituent of the 4-8 membered heterocycloalkyl is selected from methyl, ethyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is selected from -H, -CN, -C(O)NR ^e R ^f , methyl, ethyl, -CF ₃ , ethynyl, C _1-4 hydroxyalkyl, Methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, unsubstituted or 5-membered heteroaryl substituted by 1 substituent, or unsubstituted or 1 or 2 identical or different A 5-6 membered heterocycloalkyl group substituted with a substituent; the 5-membered heteroaryl group contains 2 to 3 heteroatoms selected from N; the 5-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from O Heteroatom; the substituent of the 5-membered heteroaryl group is selected from methyl, ethyl, isopropyl, -CF ₃ , or -CD ₃ ; the substituent of the 5-6 membered heterocycloalkyl group is selected from methyl, Ethyl, or -OH; ^Re , ^Rf , and ^Rg are each independently selected from -H, methyl, or ethyl.

In some embodiments, R ₁₄ is selected from , tertiary butyl, isopropyl, , , , , , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In some embodiments, R ₁₄ is selected from , , , , , , , , , tertiary butyl, isopropyl, , , , , , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

In some embodiments, R ₁₄ is selected from , , , , , , cyclobutyl, , , , , , , , , , , , , , , , , , , , , , , , ,or .

In some embodiments, R ₁₄ is selected from , , , , , , , , , , , ,or .

In some embodiments, R ₁₄ is selected from , , , ,or .

In some embodiments, R ₁₄ is selected from .

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (2): [Chemical Formula 10 ] Formula (2) wherein R ₁₁ , R ₁₂ and R ₁₃ are as defined above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (2-A): [ Chemical formula 11] Formula (2-A) wherein R ₁₃ is as defined above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (2-Aa): [ Chemical formula 12] Formula (2-Aa) wherein R ₁₃ is as defined above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (2-Ab): [ Chemical formula 13] Formula (2-Ab) wherein R ₁₃ is as defined above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (3): [Chemical Formula 14 ] Formula (3) where R ₁₄ is defined as mentioned above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (4): [Chemical Formula 15 ] Formula (4) where R ₁₄ is defined as described above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (5): [Chemical Formula 16 ] Formula (5) where R ₁₄ is defined as mentioned above.

In some embodiments, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure represented by formula (6): [Chemical Formula 17 ] Formula (6) wherein R ₁₃ and R ₁₄ are as defined above.

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

In the present invention, when R ₄ is selected from substituted or unsubstituted 4-14-membered heterocycloalkyl or 4-10-membered heterocycloalkyl, it means that there are 4-14 or 4-10 ring atoms on the ring, and the ring atoms are Carbon atoms or heteroatoms. 4-14-membered heterocycloalkyl or 4-10-membered heterocycloalkyl includes monocyclic, bicyclic, or tricyclic, and bicyclic or tricyclic includes fused, spiro, or bridged rings; if it is bicyclic or tricyclic, heterocyclic Atoms can be in any of the rings, or in two or three rings at the same time.

In the present invention, R ₁₅ and R ₁₆ and the carbon atoms to which they are connected form a 3-10-membered heterocycloalkyl group or a 3-8-membered heterocycloalkyl group that is unsubstituted or substituted by one or more identical or different substituents. or 4-8-membered heterocycloalkyl, it means that there are 3-10, 3-8 or 4-8 ring atoms in the ring, and the ring atoms are carbon atoms and heteroatoms. 3-10-membered heterocycloalkyl, 3-8-membered heterocycloalkyl or 4-8-membered heterocycloalkyl includes monocyclic, bicyclic or tricyclic rings, and bicyclic or tricyclic rings include fused, spiro or bridged rings .

In the present invention, when R ₄ is selected from substituted or unsubstituted C _3-14 cycloalkyl, C _3-12 cycloalkyl or C _3-10 cycloalkyl, it means that there are 3-14, 3-12 or 3–10 ring atoms, the ring atoms being carbon atoms. C _3-14 cycloalkyl, C _3-12 cycloalkyl or C _3-10 cycloalkyl includes monocyclic, bicyclic or tricyclic rings, and bicyclic or tricyclic rings include fused rings, spiro rings or bridged rings.

In the present invention, R ₁₅ and R ₁₆ and the carbon atoms to which they are connected form a C _3-12 cycloalkyl group, a C 3-10 cycloalkyl group, or a C _3-10 cycloalkyl group that is unsubstituted or substituted by one or more identical or different substituents. In the case of _3-8 cycloalkyl or C _4-7 cycloalkyl, it means that there are 3-12, 3-10, 3-8 or 4-7 ring atoms on the ring, and the ring atoms are carbon atoms. C _3-12 cycloalkyl, C _3-10 cycloalkyl, C _3-8 cycloalkyl or C _4-7 cycloalkyl include monocyclic, bicyclic or tricyclic rings, and bicyclic or tricyclic rings include fused rings and spiro rings. ring, or bridge ring.

Technical terms of the invention:

In the present invention, the term "optional" means that it may or may not be replaced by the following parts. For example, "-CH ₂ - on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -" can be understood It can also be understood as "-CH ₂ - on the 5-6 membered heterocycloalkyl ring can be replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -" It means "-CH ₂ - on the 5-6 membered heterocycloalkyl ring is not replaced".

In the present invention, the term "substituted" means that an atom or atomic group formally replaces hydrogen and is connected to another group as a "substituent". Unless otherwise indicated, the term "substituted" refers to any degree of substitution where such substitution is permitted, such as mono-, di-, tri-, tetra- or penta-substitution. Substituents are selected independently, and substitution can be at any chemically accessible position. It should be understood that substitution on a given atom is limited by valence. It is understood that substitution on a given atom results in a chemically stable molecule.

In the present invention, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that may be linear or branched. The term "C _1-10 alkyl" refers to an alkyl group having 1 to 10 carbon atoms. Alkyl corresponds formally to an alkane in which a CH bond is replaced by the point of attachment of the alkyl group to the rest of the compound. In some embodiments, alkyl groups contain 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms . Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, or tertiary butyl; higher homologues , such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl, etc.

In the present invention, the term "alkynyl" used alone or in combination with other terms refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group corresponds formally to an alkyne in which a CH bond is replaced by the point of attachment of the alkyl group to the rest of the compound. The term "C _2-8 alkynyl" refers to an alkynyl group having 2 to 8 carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. 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.

In the present invention, the term "alkoxy" used alone or in combination with other terms refers to a group having the formula -O-alkyl, where the term "alkyl" is as defined above. The term "C _1-8 alkoxy" refers to an alkoxy group, the alkyl group of which has 1 to 8 carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy), tertiary butoxy, and the like. In some embodiments, an alkyl group has 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms.

In the present invention, the term "halo" or "halogen" used alone or in combination with other terms refers to F, Cl, Br or I. In some embodiments, the term "halo" refers to a halogen atom selected from F, Cl, or Br.

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

In the present invention, the term "deuterated alkyl" used alone or in combination with other terms refers to an alkyl group substituted by one or more deuterium atoms, where the term "alkyl" is as defined above.

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

In the present invention, the term "heteroatom" used alone or in combination with other terms includes B, P, S, O or N.

In the present invention, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (for example, having two fused rings). The term "C _6-10 aryl" refers to an aryl group having 6 to 10 ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, indenyl, indenyl, and the like. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 10 carbon atoms. In some embodiments, aryl is phenyl. In some embodiments, aryl is naphthyl.

In the present 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, a heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, a heteroaryl group has 5 to 14 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, a heteroaryl group has 5 to 10 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O, and N. In some embodiments, a heteroaryl group has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from S, O, and N. In some embodiments, heteroaryl is a five- or six-membered heteroaryl ring. In other embodiments, the heteroaryl group is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyridyl, pyrrolyl, pyrrolyl, pyrazolyl, azolyl, thiazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinoline base, isoquinolinyl, 㖠ridinyl (including 1,2-㖠ridinyl, 1,3-㖠ridinyl, 1,4-㖠ridinyl, 1,5-㖠ridinyl, 1,6-㖠ridinyl, 1,7 -Didine, 1,8-Didine, 2,3-Didine, or 2,6-Didine), indolyl, benzothienyl, benzofuranyl, benzisothiazolyl, imidazolyl [1,2- b ]thiazolyl, purinyl, etc.

In the present invention, the term "cycloalkyl" used alone or in combination with other terms refers to non-aromatic hydrocarbon ring systems (monocyclic, bicyclic or polycyclic), including cyclized alkyl 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 may include monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbons (C _3-14 ). In some embodiments, cycloalkyl 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 members. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. In some embodiments, cycloalkyl is C _3-8 monocyclic cycloalkyl. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, norpinyl, norcarbyl, bicyclo[1.1.1]pentyl, bicyclo[2.1 .1]Hexyl, etc. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In the present invention, the term "heterocycloalkyl" used alone or in combination with other terms refers to a non-aromatic ring or ring system having at least one heteroatom ring independently selected from B, P, N, S or O member, and it has 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6- or 7-membered heterocycloalkyl groups. Heterocycloalkyl groups may include monocyclic or bicyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from N, S, or O. Heterocycloalkyl groups may be attached via ring carbon atoms or ring heteroatoms. Examples of heterocycloalkyl groups include azinoyl, azaspiro[4.5]decane, N-morpholinyl, 3-oxo-9-azaspiro[5.5]undecyl base, piperidinyl, piperazyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or scopolanoyl.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those with ordinary knowledge in the technical field to which the present invention belongs, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the specific embodiments to which the present invention belongs. There are equivalent alternatives well known to those of ordinary skill in the technical field, and preferred implementations include but are not limited to the embodiments of the present application.

The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent, which must be suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compound of the present application, it is sometimes necessary for those with ordinary knowledge in the technical field to which the present invention belongs to modify or select the synthesis steps or reaction procedures based on the existing embodiments.

An important consideration in the planning of synthetic routes in this field is the selection of appropriate protecting groups for reactive functional groups (such as the amine group in this application). For example, please refer to Chem. Commun. , 2019 , 55, 7331-7334. All references cited in this application are incorporated into this application in their entirety. Or a combination of synthetic methods known in the art and the method of the present invention can be used. The product obtained in each reaction step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be routinely synthesized according to literature (such as those provided by Scifinder) or purchased.

In some embodiments, the compound of general formula (I) of the present application (i.e. G) can be prepared by a person with ordinary knowledge in the field of organic synthesis through the following route and using standard methods in the art:

Route 1: [Chemical Formula 18] Step 1: The compound represented by formula A and the compound represented by formula B are ester exchanged under alkaline conditions to obtain the compound represented by formula C; Step 2: The compound represented by formula C and the compound represented by formula D undergo Friedel-Crafts reaction under Lewis acid conditions Obtain the compound of formula E; Step 3: The compound represented by formula E and NFSI undergo CH amination reaction under the catalysis of nitrogen oxide compound to obtain the compound of formula F; and Step 4: The compound represented by formula F is removed from the protecting group under acidic conditions to obtain Compounds of formula G; wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined in the present invention.

Route 2: [Chemical Formula 19] Step 1: Friedel-Crafts reaction occurs between the compound represented by formula C and the compound represented by formula D-1 under Lewis acid conditions to obtain the compound represented by formula J; Step 2: The compound represented by formula J undergoes hydrolysis reaction under alkaline conditions to obtain formula The compound represented by K; Step 3: The compound represented by the formula K and the compound represented by the formula B-1 undergo a condensation reaction to obtain the compound represented by the formula E; Step 4: The compound represented by the formula E and NFSI are generated under the catalysis of nitrogen oxide compounds CH amination reaction obtains the compound represented by formula F; and step 5: the compound represented by formula F removes the protecting group under acidic conditions to obtain the compound represented by formula G; wherein, R ₁ , R ₂ , R ₃ and R ₄ are as follows defined by invention.

Route 3: [Chemical Formula 20] Step 1: The compound represented by formula J and NFSI undergo a CH amination reaction under the catalysis of nitrogen oxide compounds to obtain the compound represented by formula L; Step 2: The compound represented by formula L is removed from the protecting group under acidic conditions to obtain the compound represented by formula M. Compound; Step three: The compound represented by formula M undergoes a hydrolysis reaction under alkaline conditions to obtain the compound represented by formula N; and step four: The compound represented by formula N and the compound represented by formula B-1 undergo a condensation reaction to obtain the compound represented by formula G. Compounds shown; wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined in the present invention.

In some embodiments, the compound of the general formula (1) of the present application (i.e. G-a) can be prepared by a person with ordinary knowledge in the field of organic synthesis through the following route and using standard methods in the art:

Route 1: [Chemical Formula 21] Step 1: The compound represented by formula Aa and the compound represented by formula Ba are ester exchanged under alkaline conditions to obtain the compound represented by formula Ca; Step 2: The compound represented by formula Ca and the compound represented by formula Da undergo Friedel-Crafts reaction under Lewis acid conditions Obtain the compound of formula Ea; Step 3: The compound represented by formula Ea and NFSI undergo CH amination reaction under the catalysis of nitrogen oxide compound to obtain the compound of formula Fa; and Step 4: The compound represented by formula Fa is obtained by removing the protecting group under acidic conditions Compound of formula Ga;

Among them, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are as defined in the present invention.

Route 2: [Chemical Formula 22] Step 1: Friedel-Crafts reaction occurs between the compound represented by formula Ca and the compound represented by formula D-2 under Lewis acid conditions to obtain the compound represented by formula Ja; Step 2: The compound represented by formula Ja undergoes hydrolysis reaction under alkaline conditions to obtain formula The compound represented by Ka; Step 3: The compound represented by the formula Ka and the compound represented by the formula B-2 undergo a condensation reaction to obtain the compound represented by the formula Ea; Step 4: The compound represented by the formula Ea and NFSI are generated under the catalysis of nitrogen oxide compounds CH amination reaction obtains the compound represented by formula Fa; and step five: the compound represented by formula Fa is removed from the protecting group under acidic conditions to obtain the compound represented by formula Ga; wherein, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are as follows defined by invention.

Route 3: [Chemical Formula 23] Step 1: The compound represented by formula Ja and NFSI undergo a CH amination reaction under the catalysis of nitrogen oxide compounds to obtain the compound represented by formula La; Step 2: The compound represented by formula La is removed from the protecting group under acidic conditions to obtain the compound represented by formula Ma. Compound; Step 3: The compound represented by the formula Ma undergoes a hydrolysis reaction under alkaline conditions to obtain the compound represented by the formula Na; and Step 4: The compound represented by the formula Na and the compound represented by the formula B-2 undergo a condensation reaction to obtain the compound represented by the formula Ga. Compounds shown; wherein, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are as defined in the present invention.

The present invention also provides a pharmaceutical composition, which contains the above formula (I), formula V, formula V-a, formula V-a-a, formula V-a-b, formula VI, formula VII, formula VIII, formula (1), formula (2), formula (2-A), formula (2-A-a), formula (2-A-b), formula (3), formula (4), formula (5) or formula (6) compounds, their prodrugs, solvates, crystals forms, pharmaceutically acceptable salts, stereoisomers or tautomers and pharmaceutically acceptable auxiliary ingredients.

The invention also provides the above formula (I), formula V, formula V-a, formula V-a-a, formula V-a-b, formula VI, formula VII, formula VIII, formula (1), formula (2), formula (2-A), formula (2-A-a), formula (2-A-b), formula (3), formula (4), formula (5) or formula (6) compounds, their prodrugs, solvates, crystal forms, and pharmaceutically acceptable salts , stereoisomers or tautomers or the use of the above pharmaceutical composition in the preparation of drugs for anti-HBV infection.

The present invention also provides a method for anti-HBV infection by administering the above formula (I), formula V, formula V-a, formula V-a-a, formula V-a-b, formula VI, formula VII, formula VIII, formula (1), formula (2), compounds of formula (2-A), formula (2-A-a), formula (2-A-b), formula (3), formula (4), formula (5) or formula (6), and prodrugs thereof, Solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers or pharmaceutical compositions as described above.

Beneficial effects of the present invention:

The compound of the present invention has excellent anti-HBV activity and corresponding cell proliferation inhibitory activity, and the exposure in the target organ liver is maintained at a high and stable level. It has a longer half-life, better pharmaceutical properties, and high solubility. Unexpected technical results were achieved.

The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those with ordinary skill in the technical field to which the present invention belongs, including the embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and the technology to which the present invention belongs. There are equivalent alternatives well known to those skilled in the art, and preferred embodiments include, but are not limited to, embodiments of the present invention. It will be apparent to those of ordinary skill in the art that various changes and improvements can be made to the embodiments of the invention without departing from the spirit and scope of the invention.

The abbreviations used in this application and their corresponding Chinese names are as follows: HATU: hexafluorophosphoric acid-2-(7-azenotriazole) -N , N , N ', N' -tetramethylurea NFSI: N -fluorine TEMPO: 2,2,6,6-tetramethylpiperidine oxide DMSO: dimethylsulfoxide DCM: dichloromethane DCE: dichloroethane EA: ethyl acetate TfOH: DMF trifluoromethanesulfonate: N , N -dimethylformamide LiHMDS: Lithium bis(trimethylsilyl)amide THF: Tetrahydrofuran DIEA: N , N -diisopropylethylamine NMP: N -methane Pyrrolidone PE: Petroleum ether DAST: Diethylamine sulfur trifluoride DIPEA: Diisopropylethylamine Ruphos: 2-Dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′ -BiphenylTMS-N ₃ : Azidotrimethylsilane

Example 1

Synthetic route [Chemical Formula 24]

steps 1 : compound 1-b Synthesis

Add 1-a (2 g, 13.05 mmol) into the two-necked flask, add N , N -dimethylformamide (10 mL) to dissolve, then cool to 0°C, and add sodium hydride under nitrogen protection. (1.0 g, 26.1 mmol), stir in an ice-water bath for 40 minutes, add methyl iodide (0.97 mL, 15.67 mmol) at 0°C, then stir at room temperature for 2 hours, slowly pour the reaction solution into ice water (100 mL), stir for 2 minutes, extract the aqueous phase (3×50 mL) with ethyl acetate, combine the organic layers, add saturated brine (20 mL) to wash, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , 2.4 g of light yellow transparent oily product compound 1-b was finally obtained. MS m/z(ESI): 167.1 [M−1] ⁻ .

steps 2 : compound 1-d Synthesis

Add 1-b (1.2 g, 7.18 mmol) into the two-necked flask, add tetrahydrofuran (20 mL) to dissolve, add 1-c (1.00 mL, 10.05 mmol) at room temperature, and then under nitrogen protection, incubate at 25 Add lithium bis(trimethylsilyl)amide (21.53 mL, 21.5 mmol) dropwise at 25°C. After the reaction is about 1.5 hours at 25°C, pour the reaction solution into ice water (20 mL). , the mixture was extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and added to the obtained solid A small amount of ethyl acetate was added, and the resulting mixture was filtered with a suction funnel and washed with a small amount of ethyl acetate, finally obtaining 1.3 g of white solid compound 1-d. MS m/z(ESI): 249.1 [M−1] ⁻ .

Example 2 [Chemical Formula 25] Compound 2

Synthetic route [Chemical Formula 26]

steps 1 : compound 2-c Synthesis

Add 2-a (3 g, 26.53 mmol) into the reaction flask, add methylene chloride (18 mL) to dissolve, then add N , N -diisopropylethylamine (5.3 mL, 31.8 mmol) in an ice water bath. Then 2-b (3.3 mL, 29.18 mmol) was added dropwise. After the dropwise addition, the reaction was carried out at 25°C for about 3 hours. Water was added to quench the reaction. The aqueous phase of the mixture was extracted with ethyl acetate (3×50 mL), and the organic layers were combined. , washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to finally obtain 5.6 g of the product compound 2-c as a red transparent oil. MS m/z(ESI): 212.1 [M−1] ⁻ .

steps 2 : compound 2-d Synthesis

Add 2-c (5.6 g, 26.27 mmol) into the reaction flask, add ethanol (40 mL) to dissolve, then add sodium hydroxide (3.2 g, 78.8 mmol) in water (5 mL) at 0°C, 0 The reaction is complete after about 2 hours at °C. After filtration, the filter cake is washed with ethanol to obtain a white solid. The pH of the filtrate is adjusted to about 2. The ethanol is concentrated, and the aqueous phase is extracted with ethyl acetate (3 × 30 mL). The organic phases are combined. , washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and combined the filter cakes to obtain 3.2 g of white solid compound 2-d. MS m/z(ESI): 184.1 [M−1] ⁻ .

steps 3 : compound 2-e Synthesis

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

steps 4 : compound 2-f Synthesis

Add 1-d (0.5 g, 2 mmol) into the reaction flask, add methylene chloride (10 mL) to dissolve, then add 2-e (0.61 g, 3 mmol) and aluminum trichloride (0.67 g) in an ice water bath. , 5 mmol), react at room temperature for about 1 hour, add water to the reaction solution to quench the reaction, concentrate the methylene chloride under reduced pressure, extract the residue with ethyl acetate (3 × 30 mL), and combine the organic phases , add saturated brine (15 mL) to wash, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate the organic phase under reduced pressure to obtain 0.6 g of yellow solid compound 2-f. MS m/z(ESI): 416.1 [M−1] ⁻ .

steps 5 : compound 2-g Synthesis

2-f (0.4 g, 0.96 mmol), N -fluorobis(benzenesulfonyl)imine (0.6 g, 1.92 mmol), oxy-2,2,6,6-tetramethylpiperidine (0.03 g , 0.19 mmol) into the reaction flask, add ethyl acetate (5 mL) to dissolve, raise the temperature to 50°C and react for 3 hours. After concentration, the residue is purified through a C18 column. The purification ratio is 50% (acetonitrile): 50%. (Ultrapure water [0.005%/L formic acid]) – 68% (acetonitrile): 32% (ultrapure water [0.005%/L formic acid]), collect the purified product and concentrate under reduced pressure to obtain approximately 0.32 g of a yellow solid product compound 2-g. MS m/z(ESI): 711.1 [M−1] ⁻ .

steps 6 : compound 2 Synthesis

Add 2-g (0.32 g, 0.45 mmol) into the reaction flask, dissolve it in dichloroethane (4 mL), add trifluoromethanesulfonic acid (0.08 mL, 0.9 mmol), raise the temperature to 80°C, and stir the reaction After 2 hours, the concentrated residue was purified through a C18 column. The eluent ratio was: 65% (acetonitrile): 35% (ultrapure water [0.005%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water). Pure water (0.005%/L formic acid)), collect the purified product, and concentrate under reduced pressure to obtain about 0.08 g of yellow solid product compound 2. MS m/z(ESI): 431.1 [M−H] ⁻ .

¹ H NMR (600 MHz, DMSO) δ 10.18 (s, 1H), 9.20 (d, J = 8.8 Hz, 1H), 7.83 (ddd, J = 13.8, 7.8, 2.0 Hz, 1H), 7.42 – 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 = 7.1 Hz, 3H).

Example 3 [Chemical Formula 27] Compound 3

Synthetic route [Chemical Formula 28]

steps 1 : compound 3-a Synthesis

Add 1-d (0.5 g, 2 mmol) into the reaction flask, add methylene chloride (10 mL) to dissolve, then add 2-b (0.68 g, 5 mmol) and aluminum trichloride (0.8 g) in an ice water bath. , 6 mmol), react at room temperature for about 1 hour, add water to the reaction solution to quench the reaction, concentrate the methylene chloride under reduced pressure, extract the residue with ethyl acetate (3 × 30 mL), and combine the organic phases , washed with saturated brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic phase was concentrated under reduced pressure to obtain 0.56 g of brown solid compound 3-a. MS m/z(ESI): 349.1 [M−1] ⁻ .

steps 2 : compound 3-b Synthesis

Add 3-a (0.56 g, 1.59 mmol) into the reaction flask, add ethanol (5 mL) to dissolve, then add sodium hydroxide (0.19 g, 4.8 mmol) in water (1 mL) at 0°C, 0 After reacting for about 2 hours at °C, more solids were generated and the reaction was stopped. After filtering to obtain the solids, the remaining solution was washed with ethyl acetate (2×20 mL), then the organic layer was separated, and the pH of the aqueous phase was adjusted to about 2. Concentrate, extract the aqueous phase with ethyl acetate (3 × 30 mL), combine the organic phases, add saturated brine (20 mL) to wash, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, combine the obtained products, and continue to reduce Concentrate under pressure to obtain 0.313 g of red solid compound 3-b. MS m/z(ESI): 321.1 [M−1] ⁻ .

steps 3 : compound 3-d Synthesis

Add 3-b (0.31 g, 0.97 mmol) into the reaction flask, add N , N -dimethylformamide (15 mL) to dissolve, then add hexafluorophosphoric acid-2-(7-azbenzotriazole) - N , N , N ', N' -tetramethylurea (0.96 g, 2.5 mmol) and N , N -diisopropylethylamine (0.48 mL, 2.9 mmol), and finally 3-c (0.07 mL, 1.07 mmol), after reacting at 25°C overnight, add water (50 mL) to quench the reaction, and extract the mixture with ethyl acetate (2 × 20 mL). Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the product was purified with a silica gel column. The eluate ratio was: petroleum ether: ethyl acetate = 7%: 93% ~ 12%: 88%. After the product was concentrated under reduced pressure and purified, 0.21 g of eluent was finally obtained. Yellow product compound 3-d. MS m/z(ESI): 358.1 [M−1] ⁻ .

steps 4 : compound 3-e Synthesis

3-d (0.19 g, 0.53 mmol), N -fluorobis(benzenesulfonyl)imine (1.66 g, 5.26 mmol), oxy-2,2,6,6-tetramethylpiperidine (0.016 g , 0.11 mmol) into the reaction flask, add ethyl acetate (5 mL) to dissolve, raise the temperature to 50°C and react for 5 hours. After concentration, the residue is purified through a silica gel column. The eluent ratio is: petroleum ether: ethyl acetate. Ester = 5%: 95% ~ 25%: 75%. After concentrating and purifying the product under reduced pressure, about 0.2 g of yellow solid product compound 3-e was obtained. MS m/z(ESI): 653.1 [M−1] ⁻ .

steps 5 : compound 3 Synthesis

Add 3-e (0.17 g, 0.25 mmol) into the reaction flask, dissolve it in dichloroethane (2.5 mL), add trifluoromethanesulfonic acid (0.045 mL, 0.5 mmol), raise the temperature to 80°C, and stir the reaction After 2 hours, the concentrated residue was purified through a C18 column. The eluate ratio was: 70% (acetonitrile): 30% (ultrapure water [0.005%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water). Pure water (0.005%/L formic acid)), collect the purified product, and concentrate under reduced pressure to obtain about 0.045 g of yellow solid product compound 3. MS m/z(ESI): 373.1 [M−1] ⁻ .

¹ H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 7.89 – 7.80 (m, 1H), 7.56 (s, 2H), 7.44 – 7.36 (m, 2H), 7.10 (d, J = 1.2 Hz , 1H), 3.42 (s, 3H), 2.40 (d, J = 1.2 Hz, 3H), 2.01 (s, 3H).

Example 4 [Chemical Formula 29] Compound 4

Synthetic route [Chemical Formula 30]

steps 1 : compound 4-c Synthesis

Add 1-b (420 mg, 2.51 mmol) into the two-necked flask, add tetrahydrofuran (3 mL) to dissolve, add 4-b (341.6 mL, 2.51 mmol) at room temperature, and then under nitrogen protection, incubate at 25 Add lithium bis(trimethylsilyl)amide (6.3 mL, 6.3 mmol) dropwise at 25°C. After the dripping is completed, react for 1.5 hours at 25°C. Pour the reaction solution into ice water (20 mL). The mixture was extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and then added to the obtained solid A small amount of ethyl acetate, suction filtration, and washing the filter residue with a small amount of ethyl acetate, finally obtaining 325 mg of white solid compound 4-c. MS m/z(ESI): 256.1 [M−1] ⁻ .

steps 2 : compound 4-e Synthesis

Add 4-c (253 mg, 0.98 mmol) into the reaction flask, add dichloromethane (6 mL), then add 2-e (800.4 mg, 3.93 mmol) and aluminum trichloride (393.2 mg, under an ice water bath, 2.9 mmol), reacted at room temperature for 2 hours under nitrogen protection. Cool in an ice-water bath, add water to quench the reaction, extract with ethyl acetate (3 × 30 mL), combine the organic phases, wash with saturated brine (15 mL), dry over anhydrous Na ₂ SO ₄ , filter, and concentrate the organic phase under reduced pressure with acetic acid Slurry with ethyl ester (2 mL), filter, and dry the filter cake to obtain 187 mg of white solid compound 4-e. MS m/z(ESI): 423.1 [M−1] ⁻ .

steps 3 : compound 4-f Synthesis

4-e (200 mg, 0.47 mmol), N -fluorobis(benzenesulfonyl)imine (445.8 mg, 1.41 mmol), oxy-2,2,6,6-tetramethylpiperidine (37.1 mg [ 0.005%/L NH ₄ HCO ₃ ])-62% (acetonitrile): 38% (ultrapure water [0.005%/L NH ₄ HCO ₃ ]), collect the purified product, and concentrate under reduced pressure to obtain approximately 175 mg of yellow solid product Compound 4-f. MS m/z(ESI): 718.1 [M−1] ⁻ .

steps 4 : compound 4 Synthesis

Dissolve 4-f (175 mg, 0.24 mmol) in dichloroethane (4 mL), add trifluoromethanesulfonic acid (0.13 mL, 0.2 mmol), heat to 80°C for 1 hour, stop the reaction, and concentrate the reaction solution. The residue is purified through a C18 column. The eluent ratio is: 30% (acetonitrile): 70% (ultrapure water [0.005%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water [0.005%/L] L formic acid), collect the purified product, and concentrate under reduced pressure to obtain 20 mg of yellow solid product compound 4. MS m/z(ESI): 438.1 [M−1]-

1H NMR (600 MHz, DMSO) δ 10.30 (s, 1H), 9.22 (d, J = 8.4 Hz, 1H), 8.18-8.16 (m, 1H), 7.96-7.93 (m, 1H), 7.51 (t, J = 9.6 Hz, 1H), 7.33 (d, J = 9.6 Hz, 1H), 4.71-4.67 (m,1H), 3.40 (s, 3H), 2.12 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H).

Example 6 [Chemical Formula 31] Compound 6

Synthetic route [Chemical Formula 32]

steps 1 : compound 6-b Synthesis

The operation steps were the same as the synthesis of compound 1-b, except that methyl iodide was replaced by ethyl iodide (1.02 g, 6.53 mmol) to obtain crude colorless oily compound 6-b (1.7 g, 9.4 mmol). MS m/z(ESI): 182.1 [M+H] ⁺ .

steps 2 : compound 6-c Synthesis

The operating steps are the same as the synthesis of compound 1-d, except that 1-b is replaced by 6-b (800 mg, 4.42 mmol). LCMS monitors that after the reaction is basically completed, add water to quench the reaction, add ethyl acetate (20 mL) to extract the aqueous phase, separate the organic phase, dry over Na ₂ SO ₄ , filter, concentrate and then silica gel column chromatography (petroleum ether/acetic acid Ethyl ester = 4/1) to obtain off-white solid compound 6-c (580 mg, 2.2 mmol). MS m/z(ESI): 265.1 [M+H] ⁺ .

steps 3 : compound 6-d Synthesis

The operation steps were the same as the synthesis of compound 2-f, except that 1-d was replaced by 6-c (100 mg, 0.38 mmol) to obtain compound 6-d (190 mg, 0.4 mmol) as a yellow solid. MS m/z(ESI): 432.2 [M+H] ⁺ .

steps 4 : compound 6-e Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 6-d (160 mg, 0.37 mmol) to obtain compound 6-e (50 mg, 0.07 mmol) as a yellow solid. MS m/z(ESI): 727.2 [M+H] ⁺ .

steps 5 : compound 6 Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 6-e (50 mg, 0.07 mmol) to obtain compound 6 (13 mg, 0.0 mmol) as a yellow solid. MS m/z(ESI): 447.1 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ: 10.24 (s, 1H), 9.19 (d, J = 8.8 Hz, 1H), 7.83 (ddd, J = 13.3, 7.4, 2.2 Hz, 1H), 7.51 – 7.24 (m, 4H), 4.68 (h, J = 7.6 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 2.10 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H) , 1.13 (t, J = 7.0 Hz, 3H).

Example 7 [Chemical Formula 33] Compound 7

Synthetic route [Chemical Formula 34]

steps 1 : compound 7-b Synthesis

The operating procedures were the same as the synthesis of compound 1-d, except that 3,4-difluoroaniline was replaced by 3,4,5-trifluoroaniline (492.7 mg, 3.35 mmol). After LCMS monitoring of the consumption of raw materials, add water to quench the reaction, extract with ethyl acetate (20 mL), concentrate and perform silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain yellow solid compound 7-b (660 mg, 2.5 mmol). MS m/z (ESI): 269.1 [M+H] ⁺ .

steps 2 : compound 7-c Synthesis

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

steps 3 : compound 7-d Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 7-c (260 mg, 0.6 mmol) to obtain compound 7-d (90 mg, 0.1 mmol) as a yellow solid. MS m/z(ESI): 731.0 [M+H] ⁺ .

steps 4 : compound 7 Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 7-d (90 mg, 0.1 mmol) to obtain compound 7 (10 mg, 0.0 mmol) as a yellow solid. MS m/z(ESI): 451.1 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ: 10.28 (s, 1H), 9.22 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 10.4, 6.4 Hz, 2H), 7.34 (s , 2H), 4.69 (h, J = 7.6 Hz, 1H), 3.39 (s, 3H), 2.10 (s, 3H), 1.29 (d, J = 7.1 Hz, 3H).

Example 8 [Chemical Formula 35] Compound 8

Synthetic route [Chemical Formula 36]

steps 1 : compound 8-a Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 3-a (1.66 g, 4.74 mmol) to obtain compound 8-a (3.0 g, 4.75 mmol) as a yellow solid. MS m/z(ESI): 646.1 [M+H] ⁺ .

steps 2 : compound 8-b Synthesis

Add 8-a (1.60 g, 2.48 mmol) into the reaction flask, dissolve it in 1, 2-dichloroethane (30 mL), add trifluoromethanesulfonic acid (3.94 mL, 44.61 mmol), and raise the temperature to 80° C. After stirring for 1 hour, the mixture was concentrated to obtain compound 8-b as a black oil, which was used directly in the next step. MS m/z(ESI): 366.1 [M+H] ⁺ .

steps 3 : compound 8-c Synthesis

Dissolve the crude product 8-b in a mixed solvent of ethanol (9 mL) and water (3 mL), add sodium hydroxide (0.3 g, 7.43 mmol) at 0°C, and react at 0°C for about 1 hour. LCMS monitors that after the raw materials are consumed, the pH is adjusted to about 5, and the ethanol is removed by concentration under reduced pressure. The residue is purified through a C18 column. The ratio of the eluate is: 70% (acetonitrile): 30% (ultrapure water [0.005%/L formic acid] 〕) – 50% (acetonitrile): 50% (ultrapure water [0.005%/L formic acid]), collect the purified product, and concentrate under reduced pressure to obtain orange solid compound 8-c (380 mg, 2.5 mmol). MS m/z (ESI): 338.1 [M+H] ⁺ .

steps 4 : compound 8 Synthesis

Add 8-c (60 mg, 0.18 mmol) and 8-d (24.4 mg, 0.22 mmol) into the reaction flask, add N , N -dimethylformamide (2 mL) to dissolve, then add N , N- Diisopropylethylamine (46.5 mg, 0.36 mmol), stir for one minute in an ice-water bath, add hexafluorophosphate-2-(7-azbenzotriazole) -N , N , N ′, N ′-tetramethyl Urea (82.1 mg, 0.22 mmol) was added and the reaction was carried out in an ice-water bath for half an hour. The reaction solution is directly purified through a C18 column. The eluent ratio is: 70% (acetonitrile): 30% (ultrapure water [0.005%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water [0.005%] /L formic acid]), collect the purified product, and concentrate under reduced pressure to obtain orange solid compound 8 (30 mg, 0.07 mmol). MS m/z (ESI): 432.12 [M+H] ⁺ .

1H NMR (600 MHz, DMSO) δ 10.19 (s, 1H), 9.21 (d, J = 8.8 Hz, 1H), 7.91 - 7.72 (m, 1H), 7.43 - 7.39 (m, 2H), 7.32 (s, 2H), 4.69 (m, J = 15.5, 7.7 Hz, 1H), 3.39 (s, 3H), 2.11 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H).

Example 9 [Chemical Formula 37] Compound 9

Synthetic route [Chemical Formula 38]

steps 1 : compound 9-a Synthesis

Add 4-c (4.6 g, 17.88 mmol) into the reaction flask, add methylene chloride (100 mL), add 2-b (10 mL, 89.39 mmol) and aluminum trichloride (16.7 g, 125.15 mmol), reacted at room temperature for about 2 hours under nitrogen protection, slowly added ice water (100 mL) dropwise to the reaction solution to quench it, extracted with dichloromethane (200 mL), combined the organic phases, and added saturated brine (100 mL) mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic phase was concentrated under reduced pressure to obtain off-white solid compound 9-a (4 g, 11.2 mmol). MS m/z (ESI): 358.11 [M+H] ⁺ .

steps 2 : compound 9-b Synthesis

Add 9-a (1.3 g, 3.64 mmol) and N -fluorobis(benzenesulfonyl)imine (22.9 g, 72.77 mmol) into the reaction flask, add ethyl acetate (50 mL), and then add Oxygen-2 , 2,6,6-tetramethylpiperidine (5.7 g, 36.38 mmol), under nitrogen protection, raise the temperature to 50°C and react for 18 hours, then concentrate and purify through a C18 column, elution ratio: 60% ( Acetonitrile): 40% (Ultrapure water [0.005%/L formic acid]) – 80% (Acetonitrile): 20% (Ultrapure water [0.005%/L formic acid]), collect the purified product, concentrate under reduced pressure, and obtain orange color Solid compound 9-b (2.4 g, 3.64 mmol). MS m/z (ESI): 653.0 [M+H] ⁺ .

steps 3 : compound 9-c Synthesis

Add 9-b (2.4 g, 3.64 mmol) into the reaction flask, dissolve it in 1,2-dichloroethane (20 mL), add trifluoromethanesulfonic acid (1.62 mL, 18.39 mmol), and raise the temperature to 80° C, after stirring for 20 minutes, spin off the solvent to obtain the crude compound 9-c as a black oil, which was directly used in the next step. MS m/z(ESI): 373.09 [M+H] ⁺ .

steps 4 : compound 9-d Synthesis

The operation steps were the same as the synthesis of compound 8-c, except that 8-b was replaced by 9-c to obtain orange solid compound 9-d (750 mg, 2.18 mmol). MS m/z (ESI): 345.05 [M+H] ⁺ .

steps 4 : compound 9 Synthesis

The operation steps are the same as the synthesis of compound 8, except that 8-c is replaced by 9-d (30 mg, 0.09 mmol) and 8-d is replaced by 9-e (12.8 mg, 0.13 mmol) to obtain compound 9 as a yellow solid (5.5 mg ,0.01 mmol). MS m/z(ESI): 422.17 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.26 (s, 1H), 9.06 (s, 1H), 8.17 (dt, J = 5.3, 2.5 Hz, 1H), 7.95 (m, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.28 (d, J = 10.1 Hz, 1H), 3.40 (s, 3H), 3.28 (d, J = 1.4 Hz, 1H), 2.38 (t, J = 7.7 Hz, 4H), 2.20 (s, 3H), 2.01 – 1.89 (m, 2H).

Example 10 [Chemical Formula 39] Compound 10

Synthetic route [Chemical Formula 40]

steps 1 : compound 10-b Synthesis

The operation steps were the same as the synthesis of compound 1-b, except that methyl iodide was replaced by deuterated methyl iodide (0.5 g, 3.26 mmol) to obtain crude compound 10-b (400 mg, 2.35 mmol) as a colorless oil. MS m/z(ESI): 171.1 [M+H] ⁺ .

steps 2 : compound 10-c Synthesis

The operating steps are the same as the synthesis of compound 1-d, except that 1-b is replaced by 10-b (400 mg, 2.35 mmol). After the LCMS monitoring reaction is basically completed, add water to quench the reaction, add ethyl acetate (20 mL) to extract the aqueous phase, separate the organic phase, dry over Na ₂ SO ₄ , filter, concentrate and then column chromatography (petroleum ether/ethyl acetate) Esters = 4/1) gave compound 10-c (340 mg, 1.34 mmol) as an off-white solid. MS m/z(ESI): 254.2 [M+H] ⁺ .

steps 3 : compound 10-d Synthesis

The operation steps were the same as the synthesis of compound 2-f, except that 1-d was replaced by 10-c (100 mg, 0.39 mmol) to obtain compound 10-d (114 mg, 0.27 mmol) as a yellow solid. MS m/z(ESI): 421.3 [M+H] ⁺ .

steps 4 : compound 10-e Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 10-d (114 mg, 0.27 mmol) to obtain compound 10-e (50 mg, 0.07 mmol) as a yellow solid. MS m/z(ESI): 716.5 [M+H] ⁺ .

steps 5 : compound 10 Synthesis

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.18 (s, 1H), 9.21 (d, J = 8.8 Hz, 1H), 7.89 – 7.74 (m, 1H), 7.45 – 7.26 (m, 4H), 4.74 – 4.60 (m, 1H), 2.10 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H).

Example 11 [Chemical Formula 41] Compound 11

Synthetic route [Chemical Formula 42]

steps 1 : compound 11-b Synthesis

Add 7-b (900 mg, 3.37 mmol) into the reaction flask, add methylene chloride (10 mL) to dissolve, then add 2-b (10.05 g, 7.75mmol) and aluminum trichloride (1.3 g) in an ice water bath. , 10.1 mmol), after reacting at room temperature for about 1 hour, add water to the reaction solution to quench the reaction, extract with dichloromethane (3×30 mL), combine the organic phases, add saturated brine (15 mL) and wash, After drying over anhydrous Na ₂ SO ₄ and filtering, the organic phase was concentrated under reduced pressure to obtain yellow solid compound 11-b (1.67 g, 4.53 mmol). MS m/z(ESI): 369.1 [M+H] ⁺ .

steps 2 : compound 11-c Synthesis

Add 11-b (1.67 g, 4.53 mmol) to the reaction flask, add EtOH (30 mL), add NaOH (2.2 g, 54.30 mmol) in H ₂ O (15 mL) under an ice water bath, react at room temperature for 2 hours, LCMS Monitor the completion of the reaction. After extracting impurities with ethyl acetate, adjust the pH of the aqueous phase to about 5 with dilute hydrochloric acid, add ethyl acetate for extraction, and concentrate to obtain compound 11-c (870 mg, 2.56 mmol) as a white solid. MS m/z(ESI): 339.4 [M−H] ⁻ .

steps 3 : compound 11-d Synthesis

Add 11-c (500 mg, 1.47mmol), 8-d (166 mg, 1.47mmol), DIEA (0.73 mL, 4.41 mmol) and solvent N , N -dimethylformamide (5 mL) into the reaction flask , add HATU (670.3 mg, 1.76 mmol) in an ice-water bath, slowly rise to room temperature and react for 1 hour. After the reaction is completed, LCMS monitors the reaction. Add water and precipitate a solid. The solid obtained after suction filtration is the product. After drying, a yellow solid compound 11-d is obtained. (510 mg, 1.17 mmol). MS m/z(ESI): 436.1 [M+H] ⁺ .

steps 4 : compound 11-f Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 11-d (510 mg, 1.17 mmol) to obtain compound 11-f (610 mg, 0.83 mmol) as a yellow solid. MS m/z(ESI): 731.2 [M+H] ⁺ .

steps 5 : compound 11 Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 11-f (610 mg, 0.83 mmol) to obtain compound 11 (187 mg, 0.4 mmol) as a yellow solid. MS m/z(ESI): 451.1 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.29 (s, 1H), 9.22 (d, J = 8.8 Hz, 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 = 7.0 Hz, 3H).

Example 12 [Chemical Formula 43] Compound 12

Synthetic route [Chemical Formula 44]

steps 1 : compound 12 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 12-a (11 mg, 0.10 mmol) to obtain an orange solid compound 12 (15 mg, 0.04 mmol). MS m/z (ESI): 401.12 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.16 (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 = 0.6 Hz, 1H), 2.12 (s, 3H), 1.16 – 1.13 (m, 2H), 1.02 – 0.98 (m, 2H).

Example 13 [Chemical Formula 45] Compound 13

Synthetic route [Chemical formula 46]

steps 1 : compound 13 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 13-a (13.6 mg, 0.15 mmol) to obtain compound 13 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 383.31 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.31 (s, 1H), 9.34 (t, J = 5.7 Hz, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.2 , 4.9, 2.7 Hz, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.36 (s, 2H), 4.28 (d, J = 5.7 Hz, 2H), 3.39 (s, 3H), 2.12 (s , 3H).

Example 14 [Chemical Formula 47] Compound 14

Synthetic route [Chemical formula 48]

steps 1 : compound 14 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 12-a (12 mg, 0.15 mmol) to obtain compound 14 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 408.16 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.28 (s, 1H), 9.14 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.2, 4.9, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 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).

Example 15 [Chemical Formula 49] Compound 15

Synthetic route [Chemical Formula 50]

steps 1 : compound 15 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 15-a (43 mg, 0.29 mmol) to obtain compound 15 (30 mg, 0.06 mmol) as a yellow solid. MS m/z(ESI): 440.07 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.30 (s, 1H), 9.21 (d, J = 8.8 Hz, 1H), 8.17 (dt, J = 5.2, 2.5 Hz, 1H), 7.96 – 7.93 (m, 1H ), 7.51 (t, J = 9.1 Hz, 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 = 7.1 Hz, 3H).

Example 16 [Chemical Formula 51] Compound 16

Synthetic route [Chemical Formula 52]

steps 1 : compound 16-b Synthesis

Add 16-a (4 g, 26.10 mmol) into the two-necked flask, add N , N -dimethylformamide (30 mL) to dissolve, then cool to 0°C, and add sodium hydride to it under nitrogen protection. (2 g, 52.2 mmol), stir in an ice-water bath for 40 minutes, add methyl iodide (1.95 mL, 31.14 mmol) at 0°C, then stir at room temperature for 2 hours, slowly pour the reaction solution into ice water (100 mL), stir for 2 minutes, extract the aqueous phase (3×50 mL) with ethyl acetate, combine the organic layers, add saturated brine (20 mL) to wash, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , 4.5 g of light yellow transparent oily product compound 16-b was finally obtained. MSm/z(ESI): 173.60 [M+H] ⁺ .

steps 2 : compound 16-c Synthesis

Add 16-b (2.1 g, 12.10 mmol) into the two-necked flask, add tetrahydrofuran (30 mL) to dissolve, add 1-c (2.3 g, 18.15 mmol) at room temperature, and then under nitrogen protection, incubate at 25 Add lithium bis(trimethylsilyl)amide (23.04 mL) dropwise at 25°C. After the drops are completed, react at 25°C for about 1.5 hours. Pour the reaction solution into ice water (20 mL), and then use the mixture again. Extract with ethyl acetate (3×30 mL), combine the organic phases, add saturated brine (20 mL) to wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then add a small amount of ethyl acetate to the obtained solid. ester, the obtained mixture was suction filtered, and the filter residue was washed with a small amount of ethyl acetate to obtain 2.7 g of white solid compound 16-c. MS m/z(ESI): 270.66 [M+H] ⁺ .

steps 3 : compound 16-d Synthesis

Add 16-c (2 g, 7.39 mmol) into the reaction flask, add methylene chloride (30 mL) to dissolve, then add 2-b (1.5 g, 11.08 mmol) and aluminum trichloride (2.9 g) in an ice water bath. , 22.16 mmol), react at room temperature for about 1 hour, add water to the reaction solution to quench the reaction, concentrate the methylene chloride under reduced pressure, extract the residue with ethyl acetate (3 × 30 mL), and combine the organic phases , washed with saturated brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic phase was concentrated under reduced pressure to obtain 2.3 g of off-white solid compound 16-d. MS m/z(ESI): 372.75 [M+H] ⁺ .

steps 4 : compound 16-e Synthesis

Add 16-d (2.3 g, 6.20 mmol) into the reaction flask, add ethanol (25 mL) to dissolve, add sodium hydroxide (0.7 g, 18.61 mmol) in water (3 mL) at 0°C, 0 After reacting for about 2 hours at °C, more solids were generated and the reaction was stopped. After filtering to obtain the solids, the remaining solution was washed with ethyl acetate (2×40 mL), then the organic layer was separated, and the pH of the aqueous phase was adjusted to about 2. Concentrate the ethanol, extract the aqueous phase with ethyl acetate (3 × 40 mL), combine the organic phases, add saturated brine (30 mL) to wash, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, combine the obtained products, and continue Concentrate under reduced pressure to finally obtain 1.9 g of light red solid compound 16-e. MS m/z(ESI): 341.02 [M−H] ⁻ .

steps 5 : compound 16-f Synthesis

Under ice-water bath conditions, add 16-e (500 mg, 1.46 mmol) into the reaction bottle, add N , N -dimethylformamide (5 mL) to dissolve, then add 2-a (214.7 mg, 1.90 mmol) , N , N -diisopropylethylamine (941.7 mg, 7.30 mmol), and finally hexafluorophosphate-2-(7-azenotriazole) -N , N , N ′, N ′-tetramethyl Urea (721.2 mg, 1.90 mmol). Stir in an ice-water bath for 30 min, add water (50 mL) to quench the reaction, and extract the mixture with ethyl acetate (2 × 20 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the product was purified with a silica gel column. The eluate ratio was: petroleum ether: ethyl acetate = 7%: 93% ~ 12%: 88%. After concentrating and purifying the product under reduced pressure, 0.45 g of the light yellow product compound 16 was finally obtained. -f. MS m/z(ESI): 439.77 [M+H] ⁺ .

steps 6 : compound 16-g Synthesis

16-f (450 mg, 1.03 mmol), N -fluorobis(benzenesulfonyl)imine (NFSI) (6.48.g, 20.60 mmol), oxy-2,2,6,6-tetramethylpiperdine Add TEMPO (1.61 mg, 10.30 mmol) into the reaction flask, add ethyl acetate (20 mL) to dissolve, raise the temperature to 50°C and react for 5 hours, then cool to room temperature, concentrate and pass the residue through a silica column Purification, elution ratio: petroleum ether: ethyl acetate = 5%: 95% ~ 25%: 75%. After concentrating the purified product under reduced pressure, approximately 550 mg of yellow solid compound 16-g was obtained. MS m/z(ESI): 731.05 [M−H] ⁻ .

steps 7 : compound 16 Synthesis

Add 16-g (400 mg, 0.55 mmol) into the reaction flask, dissolve it in dichloroethane (10 mL), add trifluoromethanesulfonic acid (1.49 g, 9.90 mmol), raise the temperature to 90°C, and stir the reaction After 2 hours, concentrate, and the residue is purified through a C18 column. The eluent ratio is: 70% (acetonitrile): 30% (ultrapure water [0.005%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water) Pure water (0.005%/L formic acid)), collect the purified product, and concentrate under reduced pressure to obtain about 55 mg of yellow solid compound 16. MS m/z(ESI): 452.77 [M+H] ⁺ .

1H NMR (600 MHz, DMSO) δ 10.34 (s, 1H), 9.19 (d, J = 8.4 Hz, 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 = 6.6 Hz, 3H).

Example 17 [Chemical Formula 53] Compound 17

Synthetic route [Chemical Formula 54]

steps 1 : compound 17-b Synthesis

The operation steps were the same as the synthesis of compound 16-b, except that 16-a was replaced by 17-a (2 g, 9.80 mmol), and finally 2.0 g of light yellow transparent oily product compound 17-b was obtained. MS m/z(ESI): 218.05 [M+H] ⁺ .

steps 2 : compound 17-c Synthesis

The operation steps were the same as the synthesis of compound 16-c, except that 16-b was replaced by 17-b (2 g, 9.17 mmol), and finally 2.5 g of white solid compound 17-c was obtained. MS m/z(ESI): 315.12 [M+H] ⁺ .

steps 3 : compound 17-d Synthesis

The operation steps were the same as the synthesis of compound 16-d, except that 16-c was replaced by 17-c (750 mg, 2.38 mmol) to obtain 0.85 g of brown solid compound 17-d. MS m/z(ESI): 417.21 [M+H] ⁺ .

steps 4 : compound 17-e Synthesis

The operation steps were the same as the synthesis of compound 16-e, except that 16-d was replaced by 17-d (850 mg, 2.05 mmol), and finally 0.62 g of light red solid compound 17-e was obtained. MS m/z(ESI): 384.97 [M−1] ⁻ .

steps 5 : compound 17-f Synthesis

The operation steps were the same as the synthesis of compound 16-f, except that 16-e was replaced by 17-e (620 mg, 1.60 mmol), and finally 0.45 g of the light yellow product compound 17-f was obtained. MS m/z(ESI): 484.22 [M+H] ⁺ .

steps 6 : compound 17-g Synthesis

The operation steps were the same as the synthesis of compound 16-g, except that 16-f was replaced by 17-f (0.45 g, 0.93 mmol), and about 550 mg of the yellow solid product compound 17-g was obtained. MS m/z(ESI): 775.00 [M−1] ⁻ .

steps 7 : compound 17 Synthesis

The operation steps are the same as the synthesis of compound 16, except that 16-g is replaced by 17-g (400 mg, 0.51 mmol), and about 60 mg of the yellow solid product compound 17 is obtained. MS m/z(ESI): 497.22 [M+H] ⁺ .

1H NMR (600 MHz, DMSO) δ 10.42 (s, 1H), 9.17 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 12.8, 7.4 Hz, 1H), 7.42 (t, J = 8.5 Hz , 4H), 4.70 – 4.60 (m, 1H), 3.43 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H).

Example 18 [Chemical Formula 55] Compound 18

Synthetic route [Chemical Formula 56]

steps 1 : compound 18 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 18-a (7.1 mg, 0.07 mmol) to obtain 12 mg of the pale yellow product compound 18. MS m/z(ESI): 425.46 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.25 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.19 – 8.13 (m, 1H), 7.94 (ddd, J = 7.6, 5.0, 2.6 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.26 (d, J = 10.6 Hz, 2H), 3.39 (s, 3H), 2.16 (s, 3H), 1.84 – 1.45 (m, 6H) , 1.34 – 1.04 (m, 6H).

Example 19 [Chemical Formula 57] Compound 19

Synthetic route [Chemical Formula 58]

steps 1 : compound 19 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 19-a (5.1 mg, 0.06 mmol) to obtain 10 mg of the pale yellow product compound 19. MS m/z(ESI): 411.44 [M+H] ⁺ .

1H NMR (600 MHz, DMSO) δ 10.25 (s, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.16 (dd, J = 5.7, 2.6 Hz, 1H), 7.95 – 7.89 (m, 1H) , 7.51 (t, J = 9.1 Hz, 1H), 7.26 (d, J = 10.6 Hz, 2H), 3.39 (s, 3H), 2.15 (s, 3H), 1.83 (dd, J = 12.0, 6.0 Hz, 2H), 1.64 (dd, J = 8.8, 5.9 Hz, 2H), 1.57 – 1.40 (m, 5H).

Example 20 [Chemical Formula 59] Compound 20

Synthetic route [Chemical Formula 60]

steps 1 : compound 20-a Synthesis

The operation steps were the same as the synthesis of compound 16-g, except that 16-f was replaced by 11-b (1 g, 2.72 mmol), and finally 1.2 g of the light yellow product compound 20-a was obtained. MS m/z(ESI): 662.10 [M+H] ⁻ .

steps 2 : compound 20-b Synthesis

The operation steps were the same as the synthesis of compound 16, except that 16-g was replaced by 20-a (1.2 g, 1.80 mmol) to obtain 420 mg of light yellow solid product compound 20-b. MS m/z(ESI): 384.10 [M+H] ⁺ .

steps 3 : compound 20-c Synthesis

The operation steps were the same as the synthesis of compound 16-e, except that 16-d was replaced by 20-b (420 mg, 1.09 mmol), and finally 390 mg of yellow product compound 20-c was obtained. MS m/z(ESI): 354.08 [M−H] ⁺ .

steps 3 : compound 20 Synthesis

The operation steps are the same as the synthesis of compound 16-f, except that 16-e is replaced by 20-c (50 mg, 0.14 mmol) and 2-a is replaced by 20-d (34.8 mg, 0.21 mmol) to obtain 25 mg of an orange solid. MS m/z (ESI): 501.12 [M+H] ⁺ .

1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 9.50 (s, 1H), 7.81 – 7.51 (m, 3H), 7.37 (d, J = 6.3 Hz, 2H), 3.38 (s, 3H) , 3.28 – 3.17 (m, 2H), 2.89 (td, J = 14.5, 7.8 Hz, 2H), 2.61 (d, J = 4.5 Hz, 3H), 2.13 (s, 3H)

Example 21 [Chemical Formula 61] Compound 21

Synthetic route [Chemical Formula 62]

steps 1 : compound 21-a Synthesis

The operation steps were the same as the synthesis of compound 16-c, except that 1-c was replaced by 4-b (2.4 g, 18.20 mmol), and finally 2.7 g of white solid compound 21-a was obtained. MS m/z(ESI): 270.66 [M+H] ⁺ .

steps 2 : compound 21-b Synthesis

The operation steps were the same as the synthesis of compound 16-d, except that 16-c was replaced by 21-a (2.7 g, 10.03 mmol) to obtain 2.6 g of brown-white solid compound 21-b. MS m/z(ESI): 379.77 [M+H] ⁺ .

steps 3 : compound 21-c Synthesis

The operation steps were the same as the synthesis of compound 16-e, except that 16-d was replaced by 21-b (2.6 g, 6.86 mmol), and finally 1.9 g of light red solid compound 21-c was obtained. MS m/z(ESI): 348.02 [M−H] ⁻ .

steps 5 : compound 21-d Synthesis

The operation steps were the same as the synthesis of compound 16-f, except that 16-e was replaced by 21-c (0.5 g, 1.43 mmol), and finally 0.45 g of yellow product compound 21-d was obtained. MS m/z(ESI): 446.77 [M+H] ⁺ .

steps 6 : compound 21-e Synthesis

The operation steps are the same as the synthesis of compound 16-g, except that 16-f is replaced by 21-d (0.45 g, 1.12 mmol) to obtain about 0.55 g of the yellow solid product compound 21-e. MS m/z(ESI): 740.05 [M−H] ⁻ .

steps 7 : compound twenty one Synthesis

The operation steps are the same as the synthesis of compound 16, except that 16-g is replaced by 21-e (0.55 g, 0.74 mmol), and about 55 mg of the yellow solid product compound 21 is obtained. MS m/z(ESI): 459.79 [M+H] ⁺ .

1H NMR (600 MHz, DMSO) δ 10.47 (s, 1H), 9.20 (d, J = 9.0 Hz, 1H), 8.17 (dd, J = 5.4, 2.4 Hz, 1H), 7.97-7.94 (m, 1H) , 7.53 (t, J = 10.2 Hz, 1H), 7.45 (s, 2H), 4.68-4.64 (m, 1H), 3.45 (s, 3H), 1.28 (d, J = 7.2 Hz, 3H).

Example 22 [Chemical Formula 63] Compound 22

Synthetic route [Chemical Formula 64]

steps 1 : compound 22-c Synthesis

The operating steps were the same as the synthesis of compound 2-c, except that 2-a was replaced by 22-a (1 g, 11.47 mmol) to obtain compound 22-c (2.3 g, 12.3 mmol). MS m/z(ESI): 188.14 [M+H] ⁺ .

steps 2 : compound 22-d Synthesis

The operation steps were the same as the synthesis of compound 2-d, except that 2-c was replaced by 22-c (2.3 g, 12.3 mmol) to obtain compound 22-d (2 g, 12.56 mmol). MS m/z(ESI): 160.12 [M+H] ⁺ .

steps 3 : compound 22-e Synthesis

The operation steps are the same as the synthesis of compound 2-e, except that 2-d is replaced by 22-d (150 mg, 0.94 mmol) to obtain compound 22-e, and the crude product is ready for use.

steps 4 : compound 22-f Synthesis

The operation steps were the same as the synthesis of compound 2-f, except that 2-e was replaced by 22-e (167.3 mg, 0.94 mmol) to obtain compound 22-f (160 mg, 0.4 mmol). MS m/z(ESI): 392.15 [M+H] ⁺ .

steps 5 : compound 22-g Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 22-f (160 mg, 0.4 mmol) to obtain compound 22-g (90 mg, 0.1 mmol). MS m/z(ESI): 687.16 [M+H] ⁺ .

steps 6 : compound twenty two Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 22-g (90 mg, 0.1 mmol) to obtain compound 22 (6.8 mg, 0.02 mmol). MS m/z(ESI): 407.14 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.14 (s, 1H), 8.46 (t, J = 6.2 Hz, 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 = 6.2 Hz, 2H), 2.14 (s, 3H), 0.89 (s, 9H).

Example 23 [Chemical Formula 65] Compound 23

Synthetic route [Chemical Formula 66]

steps 1 : compound 23-c Synthesis

The operation steps were the same as the synthesis of compound 2-c, except that 2-a was replaced by 23-a (0.2 g, 1.98 mmol) to obtain compound 23-c (400 mg, 1.99 mmol). MS m/z(ESI): 202.16 [M+H] ⁺ .

steps 2 : compound 23-d Synthesis

The operation steps were the same as the synthesis of compound 2-d, except that 2-c was replaced by 23-c (400 mg, 1.99 mmol) to obtain compound 23-d (362 mg, 2.1 mmol). MS m/z(ESI): 174.12 [M+H] ⁺ .

steps 3 : compound 23-e Synthesis

The operation steps are the same as the synthesis of compound 2-e, except that 2-d is replaced by 23-d (150 mg, 0.87 mmol) to obtain compound 23-e. The crude product is ready for use.

steps 4 : compound 23-f Synthesis

The operation steps were the same as the synthesis of compound 2-f, except that 2-e was replaced by 23-e (99.6 mg, 0.52 mmol) to obtain compound 23-f (160 mg, 0.4 mmol). MS m/z(ESI): 406.14 [M+H] ⁺ .

steps 5 : compound 23-g Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 23-f (160 mg, 0.4 mmol) to obtain compound 23-g (64 mg, 0.1 mmol). MS m/z(ESI): 701.15 [M+H] ⁺ .

steps 6 : compound twenty three Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 23-g (64 mg, 0.1 mmol) to obtain compound 23 (18 mg, 0.04 mmol). MS m/z(ESI): 421.15 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.18 (s, 1H), 8.26 (d, J = 9.4 Hz, 1H), 7.83 (ddd, J = 13.3, 7.5, 2.3 Hz, 1H), 7.44 – 7.32 (m, 2H), 7.28 (s, 2H), 3.76 (dq, J = 9.2, 6.8 Hz, 1H), 3.39 (s, 3H), 2.16 (s, 3H), 1.02 (d, J = 6.8 Hz , 3H), 0.89 (s, 9H).

Example 24 [Chemical Formula 67] Compound 24

Synthetic route [Chemical Formula 68]

steps 1 : compound 24-c Synthesis

The operation steps were the same as the synthesis of compound 2-c, except that 2-a was replaced by 24-a (300 mg, 2.96 mmol) to obtain compound 24-c (557 mg, 2.8 mmol). MS m/z(ESI): 202.14 [M+H] ⁺ .

steps 2 : compound 24-d Synthesis

The operation steps were the same as the synthesis of compound 2-d, except that 2-c was replaced by 24-c (557 mg, 2.8 mmol) to obtain compound 24-d (400 mg, 2.3 mmol). MS m/z(ESI): 172.3 [M−H] ⁻ .

steps 3 : compound 24-e Synthesis

The operation steps are the same as the synthesis of compound 2-e, except that 2-d is replaced by 24-d (400 mg, 2.3 mmol) to obtain compound 24-e. The crude product is ready for use.

steps 4 : compound 24-f Synthesis

The operation steps were the same as the synthesis of compound 2-f, except that 2-e was replaced by 24-e (459.7 mg, 2.4 mmol) to obtain compound 24-f (130 mg, 0.32 mmol). MS m/z(ESI): 406.21 [M+H] ⁺ .

steps 5 : compound 24-g Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 24-f (130 mg, 0.32 mmol) to obtain compound 24-g (90 mg, 0.13 mmol). MS m/z(ESI): 701.1 [M+H] ⁺ .

steps 6 : compound twenty four Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 24-g (90 mg, 0.13 mmol) to obtain compound 24 (9.1 mg, 0.02 mmol). MS m/z(ESI): 421.19 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.13 (s, 1H), 8.26 (d, J = 9.4 Hz, 1H), 7.86 – 7.79 (m, 1H), 7.43 – 7.35 (m, 2H), 7.24 (d , J = 11.2 Hz, 2H), 3.76 (dd, J = 9.4, 6.9 Hz, 1H), 3.38 (s, 3H), 2.16 (s, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H).

Example 25 [Chemical Formula 69] Compound 25

Synthetic route [Chemical Formula 70]

steps 1 : compound 25-c Synthesis

Add 25-a (400 mg, 3.14 mmol) into the reaction flask, add methylene chloride (8 mL) to dissolve, then add N , N -diisopropylethylamine (0.67 mL, 3.76 mmol) under an ice-water bath. Then 2-b (0.38 mL, 3.45 mmol) was added dropwise. After the addition was completed, the reaction was carried out at 25°C for about 2 hours. Water was added to quench the reaction. The aqueous phase of the mixture was extracted with ethyl acetate (3×20 mL), and the organic layers were combined. , washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to finally obtain 550 mg of the product compound 25-b as a yellow transparent oil. MS m/z(ESI): 226.12 [M−1] ⁻ .

steps 2 : compound 25-c Synthesis

Add 25-b (550 mg, 2.42 mmol) into the reaction flask, add ethanol (10 mL) to dissolve, then add sodium hydroxide (0.29 g, 7.2 mmol) in water (5 mL) at 0°C, 0 The reaction is complete after about 2 hours at °C. After filtration, the filter cake is washed with ethanol to obtain a white solid. The pH of the filtrate is adjusted to about 2. The ethanol is concentrated, and the aqueous phase is extracted with ethyl acetate (3 × 10 mL). The organic phases are combined. , washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 350 mg of white solid compound 25-c. MS m/z(ESI): 198.14 [M−1] ⁻ .

steps 3 : compound 25-d Synthesis

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

steps 4 : compound 25-e Synthesis

Add 1-d (0.2 g, 0.8 mmol) into the reaction flask, add methylene chloride (10 mL) to dissolve, then add 25-d (0.3 g, 1.3 mmol) and aluminum trichloride (0.33 g) in an ice water bath. , 2.5 mmol), react at room temperature for about 1 hour, add water to the reaction solution to quench the reaction, concentrate the methylene chloride under reduced pressure, extract the residue with ethyl acetate (3 × 10 mL), and combine the organic phases , washed with saturated brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic phase was concentrated under reduced pressure to obtain 0.23 g of yellow solid compound 25-e. MS m/z(ESI): 432.21 [M+H] ⁺ .

steps 5 : compound 25-f Synthesis

25-e (0.23 g, 0.53 mmol), N -fluorobis(benzenesulfonyl)imine (0.84 g, 2.67 mmol), oxy-2,2,6,6-tetramethylpiperidine (0.08 g , 0.53 mmol) into the reaction flask, add ethyl acetate (5 mL) to dissolve, raise the temperature to 50°C and react for 5 hours. After concentration, the residue is purified through a C18 column. The purification ratio is 50% (acetonitrile): 50%. (Ultrapure water [0.05%/L formic acid]) – 72% (acetonitrile): 28% (ultrapure water [0.05%/L formic acid]), collect the purified product and concentrate under reduced pressure to obtain approximately 0.025 g of yellow solid product compound 25-f. MS m/z(ESI): 727.13 [M+H] ⁺ .

steps 6 : compound 25 Synthesis

Add 25-f (0.025 g, 0.03 mmol) into the reaction flask, dissolve it in 1,2-dichloroethane (2 mL), add trifluoromethanesulfonic acid (30 mg, 0.15 mmol), and raise the temperature to 80° C. After stirring and reacting for 2 hours, the concentrated residue was purified through a C18 column. The eluent ratio was: 65% (acetonitrile): 35% (ultrapure water [0.05%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water [0.05%/L formic acid]), collect the purified product, and concentrate under reduced pressure to obtain about 0.008 g of yellow solid product compound 25. MS m/z(ESI): 447.06 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.16 (s, 1H), 8.67 (s, 1H), 7.83 (ddd, J = 13.4, 7.6, 2.1 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.26 (s, 2H), 3.39 (s, 3H), 2.15 (s, 3H), 1.55 (s, 6H).

Example 26 [Chemical Formula 71] Compound 26

Synthetic route [Chemical Formula 72]

steps 1 : compound 26 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 26-a (11 mg, 0.15 mmol) to obtain compound 26 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 393.15 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.12 (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).

Example 27 [Chemical Formula 73] Compound 27

Synthetic route [Chemical Formula 74]

steps 1 : compound 27 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 13-a (9 mg, 0.10 mmol) to obtain compound 27 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 376.13 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.34 (t, J = 5.7 Hz, 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 = 2.8 Hz, 2H), 3.39 (s, 3H), 2.10 (s, 3H).

Example 28 [Chemical Formula 75] Compound 28

Synthetic route [Chemical Formula 76]

steps 1 : compound 28 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 3-c (8.3 mg, 0.15 mmol) to obtain compound 28 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 375.14 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.17 (s, 1H), 9.00 (t, J = 5.7 Hz, 1H), 7.83 (ddd, J = 13.4, 7.0, 1.9 Hz, 1H), 7.42 – 7.37 (m , 2H), 7.30 (s, 2H), 3.96 (dd, J = 5.7, 2.5 Hz, 2H), 3.38 (s, 3H), 3.14 (t, J = 2.5 Hz, 1H), 2.12 (s, 3H) .

Example 29 [Chemical Formula 77] Compound 29

Synthetic route [Chemical Formula 78]

steps 1 : compound 29 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 29-a (8.3 mg, 0.10 mmol) to obtain compound 29 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 403.15 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.13 (s, 1H), 8.62 (s, 1H), 7.83 (ddd, J = 13.4, 7.6, 2.1 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.24 (s, 2H), 3.38 (s, 3H), 3.16 (s, 1H), 1.54 (s, 6H).

Example 30 [Chemical Formula 79] Compound 30

Synthetic route [Chemical formula 80]

steps 1 : compound 30 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 30-a (12.5 mg, 0.15 mmol) to obtain compound 30 (9 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 403.15 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.13 (s, 1H), 9.05 (s, 1H), 7.83 (ddd, J = 13.3, 7.6, 2.1 Hz, 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).

Example 31 [Chemical Formula 81] Compound 31

Synthetic route [Chemical formula 82]

steps 1 : compound 31 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 31-a (18.5 mg, 0.15 mmol) to obtain compound 31 (11 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 445.21 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.18 (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).

Example 32 [Chemical Formula 83] Compound 32

Synthetic route [Chemical formula 84]

steps 1 : compound 32 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 32-a (13.7 mg, 0.15 mmol) to obtain compound 32 (16 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 411.19 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.14 (s, 1H), 8.30 (s, 1H), 7.83 (ddd, J = 13.3, 7.5, 2.3 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.24 (s, 2H), 4.51 (d, J = 47.5 Hz, 2H), 3.38 (s, 3H), 2.17 (s, 3H), 1.30 (d, J = 2.0 Hz, 6H).

Example 33 [Chemical Formula 85] Compound 33

Synthetic route [Chemical formula 86]

steps 1 : compound 33 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 26-a (9.6 mg, 0.15 mmol) to obtain compound 33 (14 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 400.19 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.23 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 8.13 (s, 1H), 7.95 (ddd, J = 9.2, 4.9, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.23 (s, 2H), 3.39 (s, 3H), 2.20 (s, 3H), 1.32 (s, 9H).

Example 34 [Chemical Formula 87] Compound 34

Synthetic route [Chemical formula 88]

steps 1 : compound 34 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 3-c (8.2 mg, 0.15 mmol) to obtain compound 34 (10 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 382.12 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.29 (s, 1H), 9.01 (t, J = 5.7 Hz, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.2 , 4.9, 2.7 Hz, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.31 (s, 2H), 3.96 (dd, J = 5.7, 2.5 Hz, 2H), 3.39 (s, 3H), 3.14 (t, J = 2.5 Hz, 1H), 2.14 (s, 3H).

Example 35 [Chemical Formula 89] Compound 35

Synthetic route [Chemical formula 90]

steps 1 : compound 35 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 29-a (8.2 mg, 0.1 mmol) to obtain compound 35 (12 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 382.12 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.25 (s, 1H), 8.64 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 9.2, 4.9, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.25 (s, 2H), 3.39 (s, 3H), 3.16 (s, 1H), 2.19 (s, 3H), 1.54 (s, 6H) .

Example 36 [Chemical Formula 91] Compound 36

Synthetic route [Chemical formula 92]

steps 1 : compound 36 Synthesis

The operating steps were the same as the synthesis of compound 9, except that 9-e was replaced by 30-a (12.3 mg, 0.15 mmol) to obtain compound 36 (8 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 410.18 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.25 (s, 1H), 9.07 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 9.2, 4.8, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.26 (d, J = 10.0 Hz, 2H), 3.38 (s, 3H), 2.45 (s, 1H), 2.15 (s, 3H), 2.04 (s, 6H).

Example 37 [Chemical Formula 93] Compound 37

Synthetic route [Chemical Formula 94]

steps 1 : compound 37 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 31-a (18.5 mg, 0.15 mmol) to obtain compound 37 (11 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 452.12 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.30 (s, 1H), 9.37 (s, 1H), 8.16 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.2, 4.9, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.32 (s, 2H), 3.39 (s, 3H), 2.10 (s, 3H), 1.34 – 1.30 (m, 2H), 1.06 (s, 2H).

Example 38 [Chemical Formula 95] Compound 38

Synthetic route [Chemical formula 96]

steps 1 : compound 38 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 32-a (13.7 mg, 0.15 mmol) to obtain compound 38 (13 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 418.18 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.25 (s, 1H), 8.31 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 9.2, 4.9, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.26 (s, 2H), 4.51 (d, J = 47.5 Hz, 2H), 3.39 (s, 3H), 2.19 (s, 3H), 1.30 (d, J = 1.9 Hz, 6H).

Example 39 [Chemical Formula 97] Compound 39

Synthetic route [Chemical formula 98]

steps 1 : compound 39 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 24-a (13.2 mg, 0.13 mmol) to obtain 4 mg of compound 39. MS m/z(ESI): 428.18 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.27 (d, J = 9.4 Hz, 1H), 8.17 (dt, J = 5.4, 2.5 Hz, 1H), 7.94 (ddt, J = 7.8, 5.2, 2.9 Hz, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.31 – 7.21 (m, 2H), 3.77 (dq, J = 9.2, 6.8 Hz, 1H), 3.39 (s , 3H), 2.17 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H).

Example 40 [Chemical Formula 99] Compound 40

Synthetic route [Chemical formula 100]

steps 1 : compound 40 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 23-a (13.2 mg, 0.13 mmol) to obtain 8 mg of compound 40. MS m/z(ESI): 428.38 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.27 (d, J = 9.4 Hz, 1H), 8.17 (dt, J = 5.6, 2.5 Hz, 1H), 7.94 (ddt, J = 8.0, 5.1, 2.9 Hz, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.26 (d, J = 10.9 Hz, 1H), 3.77 (dq, J = 9.4, 6.8 Hz, 1H), 3.39 (s, 3H), 2.17 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H).

Example 41

[Chemical Formula 101] Compound 41

Synthetic route [Chemical formula 102]

steps 1 : compound 41 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 41-a (28 mg, 0.17 mmol) to obtain compound 41 (7.7 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 454.12 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.28 (s, 1H), 8.68 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J =9.2, 4.9, 2.7 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.28 (s, 2H), 3.40 (s, 3H), 2.17 (s, 3H), 1.55 (s, 6H)

Example 42 [Chemical Formula 103] Compound 42

Synthetic route [Chemical formula 104]

Step: Compound 42 Synthesis

Compound 105 (20 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (15.2 mg, 0.15 mmol) and methane sulfonyl chloride (10.4 mg, 0.09 mmol) were added in an ice-water bath. Stir in water bath for 3 hours. Add water to quench the reaction. Concentrate under reduced pressure to obtain a crude product, which was preparatively and purified to obtain 9.5 mg of pale yellow solid compound 42. MS m/z(ESI): 477.13 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 10.31 (s, 1H), 9.31 (d,J = 7.1 Hz, 1H), 8.17 (dd,J = 5.8, 2.7 Hz, 1H), 7.94 (m, 1H), 7.52 (t,J = 9.1 Hz, 1H), 7.36 (s, 2H), 4.59 (dd,J = 14.1, 7.2 Hz, 1H), 4.11 (t,J = 8.2 Hz, 2H), 3.90 – 3.80 (m, 2H), 3.39 (s, 3H), 3.03 (s, 3H), 2.12 (s, 3H).

Example 43 [Chemical Formula 105] Compound 43

Synthetic route [Chemical formula 106]

steps 1 : compound 43 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 20-d (9.84 mg, 0.06 mmol) to obtain 12 mg of the pale yellow product compound 43. MS m/z(ESI): 491.16 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ 10.31 (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).

Example 44 [Chemical Formula 107] Compound 44

Synthetic route [Chemical formula 108]

steps 1 : compound 44 Synthesis

The operation steps were the same as the synthesis of compound 20, except that 20-d was replaced by 44-a (23.6 mg, 0.17 mmol) to obtain orange solid compound 44 (25 mg). MS m/z (ESI): 479.11 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.34 (s, 1H), 9.76 (s, 1H), 7.60 (dd, J = 10.3, 6.4 Hz, 2H), 7.40 (s, 2H), 4.78 (q, J = 8.2 Hz, 4H), 3.39 (s, 3H), 2.16 (s, 3H)

Example 45 [Chemical Formula 109] Compound 45

Synthetic route [Chemical formula 110]

steps 1 : compound 45-a Synthesis

Dissolve 17-g (500 mg, 0.60 mmol) and methyl fluorosulfonyl difluoroacetate (1383 mg, 7.2 mmol) in NMP (50 mL), add copper iodide (381 mg, 2.0 mmol), Displacement N ₂ protection. Heating at 80°C overnight, the raw materials are consumed. Cool to room temperature, add water (100 mL) and ethyl acetate (2 × 100 mL), extract twice, wash with brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify through normal phase medium pressure (PE/EA=3 /1) to obtain 45-a (150 mg, 0.20 mmol). MS m/z (ESI): 767.08 [M+H] ⁺ .

steps 2 : compound 45 Synthesis

The operation steps are the same as the synthesis of compound 16, except that 16-g is replaced by 45-a (150 mg, 0.20 mmol) to obtain about 15 mg of the yellow solid product compound 45. MS m/z(ESI): 487.10 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.24 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 3.2 Hz, 1H), 7.58 – 7.28 (m, 4H), 4.60 (dt, J = 54.0, 23.1 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H).

Example 46 [Chemical Formula 111] Compound 46

Synthetic route [Chemical formula 112]

steps 1 : compound 46 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 46-a (25 mg, 0.18 mmol) to obtain compound 46 (2.35 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 464.15 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.29 (s, 1H), 8.90 (s, 1H), 8.17 (dt, J = 5.8, 2.4 Hz, 1H), 7.95 (ddt, J =9.2, 5.2, 2.8 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.30 (d, J = 10.1 Hz, 1H), 5.20 (t, J = 5.7 Hz, 1H), 3.56 –3.53 (m, 2H), 3.39 (s, 3H), 2.87 – 2.76 (m, 4H), 2.18 (s, 3H).

Example 47 [Chemical Formula 113] Compound 47

Synthetic route [Chemical formula 114]

steps 1 : compound 47 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 47-a (10 mg, 0.07 mmol) to obtain compound 47 (1.09 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 462.11 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.28 (s, 1H), 8.91 (s, 1H), 8.17 (dt, J = 5.3, 2.5 Hz, 1H), 7.95 (ddt, J = 7.8, 5.2, 2.9 Hz , 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.30 (d, J = 10.1 Hz, 1H), 3.40(s, 3H), 2.89 – 2.82 (m, 2H), 2.68 (q, J = 12.9 Hz, 2H), 2.18 (s, 3H), 1.84 (q, J = 7.3 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H).

Example 48 [Chemical Formula 115] Compound 48

Synthetic route [Chemical formula 116]

steps 1 : compound 48-a Synthesis

The operation steps are the same as the synthesis of compound 1-d, except that 1-b is replaced by 10-b (3 g, 17.63 mmol) and 1-c is replaced by 4-b. After the reaction was basically completed after monitoring 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 Na ₂ SO ₄ , filtered, concentrated and pulped to obtain compound 48-a (3.2 g, 12.29 mmol). MS m/z(ESI): 261.14 [M+H] ⁺ .

steps 2 : compound 48-b Synthesis

The operating steps were the same as the synthesis of compound 11-b, except that 7-b was replaced by 48-a (2.2 g, 8.45 mmol). React in an ice-water bath, monitor the completion of the reaction with LCMS, add water to the reaction solution to quench the reaction, extract with dichloromethane (3×30 mL), combine the organic phases, add saturated brine (15 mL) to wash, and anhydrous Na ₂ SO ₄ was dried, filtered, and the organic phase was concentrated under reduced pressure to obtain compound 48-b (3 g, 8.32 mmol). MS m/z(ESI): 361.12 [M+H] ⁺ .

steps 3 : compound 48-c Synthesis

The operation steps were the same as the synthesis of compound 11-c, except that 11-b was replaced by 48-b (3 g, 8.32 mmol) to obtain compound 48-c (300 mg, 0.9 mmol) as a yellow solid. MS m/z(ESI): 333.09 [M+H] ⁺ .

steps 4 : compound 48-d Synthesis

The operation steps were the same as the synthesis of compound 11-d, except that 11-c was replaced by 48-c (300 mg, 0.9 mmol) to obtain compound 48-d (250 mg, 0.58 mmol). MS m/z(ESI): 428.11 [M+H] ⁺ .

steps 5 : compound 48-e Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 48-d (250 mg, 0.58 mmol) to obtain compound 48-e (310 mg, 0.43 mmol). MS m/z(ESI): 723.13 [M+H] ⁺ .

steps 6 : compound 48 Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 48-e (310 mg, 0.43 mmol) to obtain compound 48 (60 mg, 0.14 mmol). MS m/z(ESI): 443.11 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 9.24 (d, J = 8.8 Hz, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 9.3, 4.9, 2.7 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.35 (s, 2H), 4.70 (h, J = 7.5 Hz, 1H), 2.13 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H).

Example 49 [Chemical Formula 117] Compound 49

Synthetic route [Chemical formula 118]

steps 1 : compound 49-b Synthesis

The operation steps were the same as the synthesis of compound 1-d, except that 1-c was replaced by 49-a (870.8 mg, 5.98 mmol), and finally 512 mg of yellow solid compound 49-b was obtained. MS m/z(ESI): 267.07 [M+H] ⁺ .

steps 2 : compound 49-c Synthesis

The operation steps were the same as the synthesis of compound 2-f, except that 1-d was replaced by 49-b (500 mg, 1.87 mmol) to obtain 355 mg of yellow solid compound 49-c. MS m/z(ESI): 434.07 [M+H] ⁺ .

steps 3 : compound 49-d Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 49-c (155 mg, 0.36 mmol), and finally 225 mg of yellow compound 49-d was obtained. MS m/z(ESI): 729.15 [M+H] ⁺ .

steps 4 : compound 49 Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 49-d (225 mg, 0.31 mmol), and 20 mg of yellow product compound 49 was finally obtained. MS m/z(ESI): 449.05 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.17 (s, 1H), 9.21 (d, J = 8.8 Hz, 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 = 7.0 Hz, 3H).

Example 50 [Chemical Formula 119] Compound 50

Synthetic route [Chemical formula 120]

steps 1 : compound 50-a Synthesis

The operation steps are the same as the synthesis of compound 9-b, except that 9-a is replaced by 21-b (0.6g, 1.58 mmol) to obtain 0.75g of brown solid compound 50-a. MS m/z(ESI): 673.31 [M+H] ⁺ .

steps 2 : compound 50-b Synthesis

The operation steps were the same as the synthesis of compound 9-c, except that 9-b was replaced by 50-a (0.6g, 0.89 mmol) to obtain compound 50-b (110 mg, 0.27 mmol) as a yellow solid. MS m/z(ESI): 393.13 [M+H] ⁺ .

steps 3 : compound 50-c Synthesis

The operation steps were the same as the synthesis of compound 9-d, except that 9-c was replaced by 50-b (110 mg, 0.27 mmol) to obtain compound 50-c (80 mg, 0.21 mmol) as a yellow solid. MS m/z (ESI): 365.21 [M+H] ⁺ .

steps 4 : compound 50 Synthesis

The operation steps are the same as the synthesis of compound 8, except that 8-c is replaced by 50-c (70 mg, 0.19 mmol) and 8-d is replaced by 50-d (57.1 mg, 0.38 mmol) to obtain compound 50 (13.2 mg) as a yellow solid ,0.02 mmol). MS m/z(ESI): 459.18 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.20 (d, J = 8.7 Hz, 1H), 8.17 (ddd, J = 5.7, 2.7, 1.4 Hz,1H), 7.96 (ddt, J = 9.3, 4.9, 2.4 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.44 (d, J = 4.1 Hz, 2H), 4.66 (q, J =7.7 Hz, 1H), 3.45 (s , 3H), 1.28 (d, J = 7.0 Hz, 3H).

Example 51 [Chemical Formula 121] Compound 51

Synthetic route [Chemical formula 122]

steps 1 : compound 51 Synthesis

The operation steps were the same as the synthesis of compound 20, except that 20-d was replaced by 51-a (58.2 mg, 0.33 mmol) to obtain an orange solid compound 51 (25 mg, 0.04 mmol). MS m/z (ESI): 512.15 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.27 (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 = 9.6 Hz, 1H), 3.38 (s, 3H), 3.24 (dd, J = 24.5, 12.8 Hz, 4H), 2.02 (s, 3H).

Example 52 [Chemical Formula 123] Compound 52

Synthetic route [Chemical formula 124]

steps 1 : compound 52-a Synthesis

The operation steps were the same as the synthesis of compound 17-c, except that 1-c was replaced by 4-b (1 g, 4.58 mmol), and finally 950 mg of white solid compound 52-a was obtained. MS m/z(ESI): 321.99 [M+H] ⁺ .

steps 2 : compound 52-b Synthesis

The operation steps were the same as the synthesis of compound 17-d, except that 17-c was replaced by 52-a (950 mg, 2.95 mmol) to obtain 0.85 g of brown solid compound 52-b. MS m/z(ESI): 422.01 [M+H] ⁺ .

steps 3 : compound 52-c Synthesis

The operation steps were the same as the synthesis of compound 17-e, except that 17-d was replaced by 52-b (850 mg, 2.05 mmol), and finally 0.57 g of light red solid compound 52-c was obtained. MS m/z(ESI): 391.08 [M−1] ⁻ .

steps 4 : compound 52-d Synthesis

The operation steps were the same as the synthesis of compound 17-f, except that 17-e was replaced by 52-c (570 mg, 1.46 mmol), and finally 0.45 g of the pale yellow product compound 52-d was obtained. MS m/z(ESI): 489.01 [M+H] ⁺ .

steps 5 : compound 52-e Synthesis

The operation steps were the same as the synthesis of compound 17-g, except that 17-f was replaced by 52-d (0.45 g, 0.92 mmol), and about 550 mg of the yellow solid product compound 52-e was obtained. MS m/z(ESI): 783.00 [M−1] ⁻ .

steps 6 : compound 52-f Synthesis

The operation steps were the same as the synthesis of compound 45-a, except that 17-g was replaced by 52-e (550 mg, 0.71 mmol) to obtain 80 mg of the yellow solid product compound 52-f. MS m/z(ESI): 774.08 [M+H] ⁺ .

steps 7 : compound 52 Synthesis

The operation steps were the same as the synthesis of compound 17, except that 17-g was replaced by 52-f (80 mg, 0.10 mmol), and about 8 mg of compound 52 was obtained as a yellow solid product. MS m/z(ESI): 494.10 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.16 (dd,J = 5.7, 2.6 Hz, 1H), 7.97 – 7.83 (m, 1H ), 7.56 (t,J = 9.1 Hz, 1H), 7.46 (s, 2H), 4.64 (dd,J = 15.1, 7.6 Hz, 1H), 3.37 (s, 3H), 1.28 (d,J = 7.0 Hz , 4H).

Example 53 [Chemical Formula 125] Compound 53

Synthetic route [Chemical formula 126]

steps 1 : 53-a Synthesis

The operation steps were the same as the synthesis of compound 16-b, except that methyl iodide was replaced by deuterated methyl iodide (1.95 mL, 31.14 mmol) to obtain 4.5 g of light yellow transparent oily product compound 53-a. MSm/z(ESI): 177.05 [M+H] ⁺ .

steps 2 : compound 53-b Synthesis

The operation steps are the same as the synthesis of compound 16-c, except that 16-b is replaced by 53-a (4.5 g, 25.42 mmol), 1-c is replaced by 4-b (4.14 g, 30.49 mmol), and 5 g of a light yellow solid compound are obtained. 53-b. MSm/z(ESI): 281.06 [M+H] ⁺ .

steps 3 : compound 53-c Synthesis

The operation steps were the same as the synthesis of compound 16-d, except that 16-c was replaced by 53-b (5 g, 17.79 mmol) to obtain 3.5 g of light yellow solid compound 53-c. MSm/z(ESI): 381.08 [M+H] ⁺ .

steps 4 : compound 53-d Synthesis

The operation steps were the same as the synthesis of compound 16-e, except that 16-d was replaced by 53-c (3.5 g, 9.18 mmol) to obtain 3.1 g of light yellow solid compound 53-d. MSm/z(ESI): 351.05 [M+H] ⁻ .

steps 5 : compound 53-e Synthesis

The operation steps were the same as the synthesis of compound 16-f, except that 16-e was replaced by 53-d (3.1 g, 8.83 mmol) to obtain 3 g of pale yellow solid compound 53-e. MSm/z(ESI): 448.08 [M+H] ⁺ .

steps 6 : compound 53-f Synthesis

The operating steps were the same as the synthesis of compound 16-g, except that 16-f was replaced by 53-e (3 g, 6.69 mmol) to obtain 3.1 g of pale yellow solid compound 53-f. MSm/z(ESI): 743.08 [M+H] ⁺ .

steps 7 : compound 53 Synthesis

The operation steps were the same as the synthesis of compound 16, except that 16-g was replaced by 53-f (3.1 g, 4.17 mmol) to obtain 350 mg of compound 53 as a light yellow solid. MSm/z(ESI): 463.09 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.46 (s, 1H), 9.19 (d, J = 8.7 Hz, 1H), 8.17 (dd, J = 5.7, 2.6 Hz, 1H), 7.95 (ddd,J = 8.9 , 4.7, 2.7 Hz, 1H), 7.53 (t,J = 9.1 Hz, 1H), 7.44 (d,J = 5.8 Hz, 2H), 4.66 (d,J = 7.6 Hz, 1H), 1.28 (d,J = 7.0 Hz, 3H).

Example 54 [Chemical Formula 127] Compound 54

Synthetic route [Chemical formula 128]

steps 1 : compound 54 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 54-a (8.5 mg, 0.07 mmol) to obtain compound 54 (5 mg, 0.01 mmol) as a yellow solid. MS m/z(ESI): 414.10 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.29 (s, 1H), 9.08 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.97-7.93 (m, 1H), 7.51 (t , J = 9.1 Hz, 1H), 7.32 (s, 2H), 4.66 (d, J = 6.3 Hz, 2H), 4.37 (d, J = 6.3 Hz, 2H), 3.40 (s, 3H), 2.20 (s , 3H), 1.57 (s, 3H).

Example 55 [Chemical Formula 129] Compound 55

Synthetic route [Chemical formula 130]

steps 1 : compound 55 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 55-a (8 mg, 0.07 mmol) to obtain compound 55 (20 mg, 0.05 mmol) as a yellow solid. MS m/z(ESI): 442.48 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.24 (s, 1H), 8.18-8.16 (m, 2H), 7.97-7.94 (m, 1H), 7.51 (t, J = 9.1 Hz, 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 ).

Example 56 [Chemical Formula 131] Compound 56

Synthetic route [Chemical formula 132]

steps 1 : compound 56 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 56-a (7.2 mg, 0.07 mmol) to obtain compound 56 (20 mg, 0.05 mmol) as a yellow solid. MS m/z(ESI): 430.17 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.25 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 8.05 (s, 1H), 7.97-7.93 (m, 1H), 7.51 (t , J = 9.1 Hz, 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) .

Example 57 [Chemical Formula 133] Compound 57

Synthetic route [Chemical formula 134]

steps 1 : compound 57 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 57-a (16.2 mg, 0.1 mmol) to obtain compound 57 (20 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 462.14 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.27 (s, 1H), 8.61 (d, J = 7.7 Hz, 1H), 8.16 (dd, J = 5.8, 2.7 Hz, 1H), 7.96-7.92 (m, 1H ), 7.51 (t, J = 9.1 Hz, 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), 1.86-1.82 m, 2H), 1.58 – 1.51 (m, 2H).

Example 58 [Chemical Formula 135] Compound 58

Synthetic route [Chemical formula 136]

steps 1 : compound 58 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 58-a (8.4 mg, 0.12 mmol) to obtain compound 58 (20 mg, 0.05 mmol) as a yellow solid. MS m/z(ESI): 444.12 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO) δ 10.27 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 5.8, 2.7 Hz, 1H), 7.96-7.92 (m, 1H ), 7.51 (t, J = 9.1 Hz, 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).

Example 59 [Chemical Formula 137] Compound 59

Synthetic route [Chemical formula 138]

steps 1 : compound 59 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 59-a (17.3 mg, 0.15 mmol) to obtain compound 59 (18 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 442.14 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 8.17 (ddd, J = 5.8, 2.7, 1.4 Hz, 1H), 7.95 ( dddd, J = 9.4, 4.8, 2.8, 2.0 Hz, 1H), 7.51 (t, J = 9.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 2H), 4.37 (s, 1H), 3.68 (dd , J = 15.5, 5.2 Hz, 2H), 3.39 (s, 3H), 2.16 (s, 3H), 1.64 (td, J = 13.6, 12.9, 4.0 Hz, 4H), 1.48 (ddd, J = 16.7, 10.1 , 3.7 Hz, 4H).

Example 60 [Chemical Formula 139] Compound 60

Synthetic route [Chemical formula 140]

steps 1 : compound 60 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 60-a (13.4 mg, 0.15 mmol) to obtain compound 60 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 416.23 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.27 (s, 1H), 8.31 – 8.25 (m, 1H), 8.17 (ddd, J = 5.8, 2.8, 1.4 Hz, 1H), 8.02 – 7.85 (m , 1H), 7.51 (t, J = 9.2 Hz, 1H), 7.29 (d, J = 7.3 Hz, 2H), 4.68 (s, 1H), 3.70 (dt, J = 8.4, 5.9 Hz, 1H), 3.43 (dd, J = 10.7, 5.3 Hz, 2H), 3.39 (s, 3H), 2.18 (s, 3H), 1.64 (dqd, J = 15.0, 7.5, 4.8 Hz, 1H), 1.38 (ddd, J = 13.6 , 8.6, 7.2 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H).

Example 61 [Chemical Formula 141] Compound 61

Synthetic route [Chemical formula 142]

steps 1 : compound 61 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 61-a (18.5 mg, 0.15 mmol) to obtain compound 61 (7 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 414.12 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.82 (d, J = 7.0 Hz, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.3, 4.9, 2.7 Hz, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.28 (d, J = 10.3 Hz, 2H), 5.04 (s, 1H), 4.27 (p, J = 4.9 Hz, 2H), 3.39 (s, 3H), 2.18 (dd, J = 7.0, 4.8 Hz, 2H), 2.13 (s, 3H), 2.12 – 2.09 (m, 1H), 2.03 – 1.96 (m, 1H) .

Example 62 [Chemical Formula 143] Compound 62

Synthetic route [Chemical formula 144]

steps 1 : compound 62 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 62-a (24.8 mg, 0.15 mmol) to obtain compound 62 (19 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 456.18 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.42 (s, 1H), 8.19 (ddd, J = 5.8, 2.7, 1.3 Hz, 1H), 7.98 (ddt, J = 7.2 , 4.8, 2.4 Hz, 2H), 7.53 (t, J = 9.2 Hz, 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).

Example 63 [Chemical Formula 145] Compound 63

Synthetic route [Chemical formula 146]

steps 1 : compound 63 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 63-a (20.6 mg, 0.15 mmol) to obtain compound 63 (20 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 464.04 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 10.31 (s, 1H), 8.40 (s, 1H), 8.19 (dd, J = 6.4, 2.6 Hz, 1H), 7.95 ( dt, J = 9.7, 2.5 Hz, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 10.9, 8.0 Hz, 2H), 7.37 (d, J = 6.4 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 3.44 (s, 3H), 2.16 (s, 3H).

Example 64 [Chemical Formula 147] Compound 64

Synthetic route [Chemical formula 148]

steps 1 : compound 64 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 64-a (11.3 mg, 0.15 mmol) to obtain compound 64 (7 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 402.13 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.19 (ddd, J = 5.9, 2.8, 1.5 Hz, 1H), 7.96 ( ddt, J = 9.4, 4.9, 2.3 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 3.87 (dt, J = 13.8, 6.7 Hz , 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 = 6.7 Hz, 3H).

Example 65 [Chemical Formula 149] Compound 65

Synthetic route [Chemical formula 150]

steps 1 : compound 65-a Synthesis

The operating steps were the same as the synthesis of compound 1-b, except that 1-a was replaced by 17-a (3 g, 14.71 mmol), and methyl iodide was replaced by deuterated methyl iodide to obtain compound 65-a (2.3 g, 10.40 mmol). MS m/z(ESI): 223.15 [M+H] ⁺ .

steps 2 : compound 65-b Synthesis

The operation steps were the same as the synthesis of compound 1-d, except that 1-b was replaced by 65-a (2.3 g, 10.40 mmol), and 1-c was replaced by 4-b, to obtain compound 65-b (1.6 g, 4.92 mmol). MS m/z(ESI): 326.99 [M+H] ⁺ .

steps 3 : compound 65-c Synthesis

The operation steps were the same as the synthesis of compound 11-b, except that 7-b was replaced by 65-b (1.6 g, 4.92 mmol) to obtain compound 65-c (2 g, 4.70 mmol). MS m/z(ESI): 426.99 [M+H] ⁺ .

steps 4 : compound 65-d Synthesis

The operating steps were the same as the synthesis of compound 11-c, except that 11-b was replaced by 65-c (2 g, 4.70 mmol) to obtain compound 65-d (1.8 g, 4.53 mmol). MS m/z(ESI): 396.2 [M−H] ⁻ .

steps 5 : compound 65-e Synthesis

The operation steps were the same as the synthesis of compound 11-d, except that 11-c was replaced by 65-d (1.8 g, 4.53 mmol) and 8-d was replaced by 2-a to obtain compound 65-e (1.8 g, 3.66 mmol). MS m/z(ESI): 490.1 [M+H] ⁺ .

steps 6 : compound 65-f Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 65-e (1.6 g, 3.25 mmol) to obtain compound 65-f (1.9 g, 2.41 mmol). MS m/z(ESI): 787.7 [M+H] ⁺ .

steps 7 : compound 65 Synthesis

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.55 (s, 1H), 9.20 (d, J = 8.7 Hz, 1H), 8.31 – 8.13 (m, 1H), 7.99 (ddt, J = 9.4, 4.7 , 2.2 Hz, 1H), 7.56 (t, J = 9.1 Hz, 1H), 7.46 (d, J = 5.0 Hz, 2H), 4.78 – 4.55 (m, 1H), 1.32 (d, J = 7.1 Hz, 3H ).

Example 66 [Chemical Formula 151] Compound 66

Synthetic route [Chemical formula 152]

steps 1 : compound 66-b Synthesis

Dissolve 66-a (1300 mg, 7.69 mmol) in anhydrous DCM (13 mL), and slowly add DAST (5.08 mL, 38.44 mmol) DCM solution (5 mL) dropwise under ice-water bath cooling. After the addition is completed, react in ice-water bath. 1 hour, react at room temperature overnight. The reaction solution was slowly dropped into ice water (50 mL), and DCM (50 mL) was added for extraction. The organic layer was washed with saturated NaHCO ₃ (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.29 g. Compound 66-b is a colorless oil.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 – 8.46 (m, 2H), 7.77 – 7.67 (m, 1H), 7.34 (t, J = 53.6 Hz, 1H).

steps 2 : compound 66-c Synthesis

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

steps 3 : compound 66-d Synthesis

The operation steps were the same as the synthesis of compound 1-d, except that 1-c was replaced by 66-c (1.0 g, 5.98 mmol), and finally 685 mg of compound 66-d was obtained as a yellow solid. MS m/z(ESI): 283.07 [M+H] ⁺ .

steps 4 : compound 66-e Synthesis

The operation steps were the same as the synthesis of compound 11-b, except that 7-b was replaced by 66-d (435 mg, 1.54 mmol), and 220 mg of yellow solid compound 66-e was finally obtained. MS m/z(ESI): 383.11 [M+H] ⁺ .

steps 5 : compound 66-f Synthesis

Add 66-e (220 mg, 0.58 mmol) into the reaction flask, dissolve in tetrahydrofuran (3 mL) and cool to 0°C. An aqueous solution (3 mL) of lithium hydroxide monohydrate (72.5 mg, 1.73 mmol) was added dropwise to the reaction solution. Stir for half an hour at 0°C. After the organic volatiles were evaporated with a rotary evaporator, the pH of the reaction solution was adjusted to about 5 with 1 M dilute hydrochloric acid, diluted with water (20 mL), extracted with ethyl acetate (2 × 20 mL), and the organic phases were combined. Wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 137 mg of product 66-f. MS m/z(ESI): 355.09 [M+H] ⁺ .

steps 6 : compound 66-g Synthesis

The operation steps are the same as the synthesis of compound 11-d, except that 11-c is replaced by 66-f (500 mg, 1.87 mmol), and 8-d is replaced by 2-a (86.7 mg, 0.58 mmol) to obtain 92 mg of a yellow solid compound. 66-g. MS m/z(ESI): 448.08 [M−H] ⁻ .

steps 7 : compound 66-h Synthesis

The operating steps were the same as the synthesis of compound 11-f, except that 11-d was replaced by 66-g (92 mg, 0.20 mmol) to obtain 200 mg of compound 66-h as a yellow oil. MS m/z(ESI): 745.09 [M+H] ⁺ .

steps 8 : compound 66 Synthesis

The operation steps were the same as the synthesis of compound 11, except that 11-f was replaced by 66-h (200 mg, 0.27 mmol), and finally 10 mg of yellow product compound 66 was obtained. MS m/z(ESI): 465.14 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.21 (s, 1H), 9.22 (d, J = 8.8 Hz, 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 = 7.1 Hz, 3H).

Example 67 [Chemical Formula 153] Compound 67

Synthetic route [Chemical formula 154]

steps 1 : compound 67-a Synthesis

Dissolve 65-f (300 mg, 0.38 mmol), methyl fluorosulfonyl difluoroacetate (0.73 mL, 5.71 mmol) and CuI (145.1 mg, 0.76 mmol) in NMP (10 mL), and store under nitrogen at 80°C. React overnight, add water to quench the reaction, extract with ethyl acetate (20 mL), concentrate and purify on a C18 column. Eluent ratio: 70% (acetonitrile): 30% (ultrapure water [0.005%/L formic acid]) – 20% (acetonitrile): 80% (ultrapure water [0.005%/L formic acid]) to obtain compound 67-a (80 mg, 0.10 mmol). MS m/z(ESI): 777.08 [M+H] ⁺ .

steps 2 : compound 67 Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 67-a (80 mg, 0.10 mmol) to obtain compound 67 (13 mg, 0.03 mmol). MS m/z(ESI): 497.23 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.23 (s, 1H), 9.27 (d, J = 8.9 Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 8.7, 5.1, 2.8 Hz, 1H), 7.59 (t, J = 9.1 Hz, 1H), 7.47 (d, J = 6.7 Hz, 2H), 4.77 – 4.51 (m, 1H), 1.31 (d, J = 7.1 Hz, 3H).

Example 68 [Chemical Formula 155] Compound 68

Synthetic route [Chemical formula 156]

steps 1 : compound 68 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 68-a (14.7 mg, 0.11 mmol) to obtain compound 68 (12 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 456.11 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (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 = 9.1 Hz, 1H), 7.49-7.41 (m, 3H), 3.44 (s, 3H), 2.13 (s, 3H).

Example 69 [Chemical Formula 157] Compound 69

Synthetic route [Chemical formula 158]

steps 1 : compound 69 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 69-a (9.06 mg, 0.06 mmol) to obtain 13 mg of pale yellow product compound 69. MS m/z(ESI): 478.22 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.17 (dd, J = 5.7, 2.5 Hz, 1H), 8.03 – 7.92 (m, 2H), 7.51 (t, J = 9.1 Hz, 1H ), 7.22 (d,J = 6.9 Hz, 2H), 3.39 (s, 3H), 2.22 (s, 3H), 2.01 (d,J = 12.2 Hz, 9H), 1.63 (s, 6H).

Example 70 [Chemical Formula 159] Compound 70

Synthetic route [Chemical formula 160]

steps 1 : compound 70 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 70-a (6.18 mg, 0.06 mmol) to obtain 9 mg of light yellow product compound 70. MS m/z(ESI): 430.18 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.17 (dd, J = 5.7, 2.6 Hz, 1H), 8.10 (s, 1H), 7.95 (ddd, J = 9.0, 4.7, 2.7 Hz , 1H), 7.50 (t, J = 9.1 Hz, 1H), 7.25 (d, J = 7.2 Hz, 2H), 3.52 (t,J = 6.9 Hz, 2H), 2.20 (s, 3H), 1.84 (t ,J = 6.9 Hz, 2H), 1.32 (s, 6H).

Example 71 [Chemical Formula 161] Compound 71

Synthetic route [Chemical formula 162]

steps 1 : compound 71 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 71-a (24.5 mg, 0.17 mmol) to obtain compound 71 (5.9 mg, 0.01 mmol) as a yellow solid. MS m/z (ESI): 468.20 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.76 (s, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.97 (ddd, J = 9.2, 4.8,2.6 Hz , 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.40 (d, J = 6.2 Hz, 2H), 4.80 (d, J = 2.1 Hz, 4H), 3.42 (s, 3H), 2.20 (s , 3H).

Example 72 [Chemical Formula 163] Compound 72

Synthetic route [Chemical formula 164]

steps 1 : compound 72 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 72-a (23.0 mg, 0.17 mmol) to obtain compound 72 (8.6 mg, 0.02 mmol) as a yellow solid. MS m/z (ESI): 458.26 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 9.48 (s, 1H), 8.19 (dd, J = 5.8, 2.6 Hz, 1H), 7.96 (ddt, J =9.4, 4.9, 2.4 Hz , 1H), 7.53 (t, J = 9.2 Hz, 1H), 7.35 (d, J = 6.3 Hz, 1H), 3.49 (s, 1H), 3.42 (s, 3H), 3.17 –3.06 (m, 4H) , 2.19 (s, 3H).

Example 73 [Chemical Formula 165] Compound 73

Synthetic route [Chemical formula 166]

steps 1 : compound 73 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 73-a (7.80 mg, 0.06 mmol) to obtain 11 mg of the pale yellow product compound 73. MS m/z(ESI): 456.20 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.16 (dd, J = 5.7, 2.4 Hz, 1H), 7.94 (m, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.25 (d, J = 7.1 Hz, 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).

Example 74 [Chemical Formula 167] Compound 74

Synthetic route [Chemical formula 168]

steps 1 : compound 74 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 74-a (19.2 mg, 0.15 mmol) to obtain compound 74 (4 mg, 0.01 mmol) as a yellow solid. MS m/z(ESI): 455.14 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 8.61 (s, 1H), 8.19 (dd,J = 3.8, 2.0 Hz, 1H), 7.96 (ddt,J = 9.3, 4.7 , 2.4 Hz, 1H), 7.53 (t,J = 9.1 Hz, 1H), 7.31 (d,J = 6.8 Hz, 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 = 6.8 Hz, 4H)

Example 75 [Chemical Formula 169] Compound 75

Synthetic route [Chemical formula 170]

steps 1 : compound 75 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 75-a (4.2 mg, 0.06 mmol) to obtain 7 mg of the pale yellow product compound 75. MS m/z(ESI): 398.41 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.80 (d,J = 7.8 Hz, 1H), 8.15 (dd, J = 5.7, 2.6 Hz, 1H), 7.93 (s, 1H), 7.50 (t,J = 9.1 Hz, 1H), 7.28 (s, 2H), 4.27 (s, 1H), 2.17 (dd,J = 6.8, 3.7 Hz, 2H), 2.12 (s, 3H), 1.97 (dd ,J = 15.0, 5.8 Hz, 2H), 1.65 (dd,J = 9.5, 4.1 Hz, 2H).

Example 76 [Chemical Formula 171] Compound 76

Synthetic route [Chemical formula 172]

steps 1 : compound 76 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 76-a (30.3 mg, 0.17 mmol) to obtain compound 76 (15.1 mg, 0.03 mmol) as a yellow solid. MS m/z (ESI): 501.10 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 14.92 (s, 1H), 10.29 (s, 1H), 9.60 (s, 1H), 8.17 (dd, J = 5.8, 2.7 Hz, 1H), 7.94 (ddd, J = 9.3, 4.9, 2.7 Hz, 1H), 7.77 (s, 1H), 7.52 (t, J = 9.1 Hz, 1H), 7.33 (d, J = 6.5 Hz, 2H), 3.40(s, 3H), 3.26 (d, J = 12.7 Hz, 4H), 2.05 (s, 3H). Example 77 [Chemical Formula 173] Compound 77

Synthetic route [Chemical formula 174]

steps 1 : compound 77-b Synthesis

The operation steps were the same as the synthesis of compound 1-d, except that 1-b was replaced by 16-b (5g, 1.58 mmol), and 1-c was replaced by 77-a, to obtain 5.5g of brown solid compound 77-b. MS m/z(ESI): 289.12 [M+H] ⁺ .

steps 2 : compound 77-d Synthesis

Add 77-b (5 g, 17.3 mmol) into the reaction flask, add methylene chloride (100 mL) to dissolve, then add 2-b (7 g, 51.9 mmol) and aluminum trichloride (7.8 g) in an ice water bath. , 51.9 mmol), react at room temperature for about 2 hours, add water to the reaction solution to quench the reaction, concentrate the methylene chloride under reduced pressure, extract the residue with ethyl acetate (3 × 50 mL), and combine the organic phases , washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic phase was concentrated under reduced pressure to obtain 5 g of brown solid compound 77-d. MS m/z(ESI): 389.12 [M+H] ⁺ .

steps 3 : compound 77-e Synthesis

Add 77-d (5g, 12.8 mmol) and N -fluorobis(benzenesulfonyl)imine (22.9 g, 72.77 mmol) into the reaction flask, add ethyl acetate (250 mL), and then add Oxygen-2, 2,6,6-Tetramethylpiperidine (5.7 g, 36.38 mmol) was heated to 50°C under nitrogen protection, reacted for 12 hours, concentrated, and passed through a silica gel column (DCM: MeOH = 100: 1 – 20: 1) System purification, purification through C18 column, elution ratio: 60% (acetonitrile): 40% (ultrapure water [0.05%/L formic acid]) – 80% (acetonitrile): 20% (ultrapure water [ultrapure water] 0.05%/L formic acid), collect the purified product, and concentrate under reduced pressure to obtain orange solid compound 77-e (8g, 3.64 mmol). MS m/z (ESI): 684.15 [M+H] ⁺ .

steps 4 : compound 77-f Synthesis

Add 77-e (3 g, 4.39 mmol) into the reaction flask, dissolve it in 1,2-dichloroethane (20 mL), add trifluoromethanesulfonic acid (1.94 mL, 21.95 mmol), and raise the temperature to 80° C, after stirring for 20 minutes, slowly add the reaction solution dropwise to the saturated sodium bicarbonate aqueous solution, collect the organic phase, concentrate, and purify through a reverse-phase C18 column. The eluate ratio: 60% (acetonitrile): 40% (ultrasonic acid) Pure water [0.05%/L formic acid]) – 80% (acetonitrile): 20% (ultrapure water [0.05%/L formic acid]), collect the purified product, and concentrate under reduced pressure to obtain yellow solid compound 77-f (0.6 g ,1.48 mmol). MS m/z(ESI): 404.31 [M+H] ⁺ .

steps 5 : compound 77-g Synthesis

Dissolve 77-f (0.6 g, 1.48 mmol) in a mixed solvent of ethanol (9 mL) and water (3 mL), add sodium hydroxide (0.3 g, 7.43 mmol) at 0°C, The reaction takes about 1 hour. LCMS monitors that after the raw materials are consumed, the pH is adjusted to about 5, and the ethanol is removed by concentration under reduced pressure. The residue is purified through a C18 column. The ratio of the eluate is: 30% (acetonitrile): 70% (ultrapure water [0.05%/L formic acid] 〕) – 60% (acetonitrile): 40% (ultrapure water [0.05%/L formic acid]), collect the purified product, and concentrate under reduced pressure to obtain orange solid compound 77-g (300 mg, 0.8 mmol). MS m/z (ESI): 376.32 [M+H] ⁺ .

steps 6 : compound 77 Synthesis

Add 77-g (60 mg, 0.18 mmol) and 77-h (39.2 mg, 0.31 mmol) into the reaction flask, add N , N -dimethylformamide (2 mL) to dissolve, then add N , N- Diisopropylethylamine (61.7 mg, 0.47 mmol), stir for one minute in an ice-water bath, add hexafluorophosphoric acid-2-(7-azbenzotriazole) -N , N , N ′, N ′-tetramethyl Urea (121.2 mg, 0.31 mmol) was added and the reaction was carried out in an ice-water bath for half an hour. The reaction solution is directly purified through a C18 column. The eluent ratio is: 20% (acetonitrile): 80% (ultrapure water [0.05%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water [0.05%] /L formic acid]), collect the purified product, and concentrate under reduced pressure to obtain yellow solid compound 77 (10 mg, 0.002 mmol). MS m/z (ESI): 445.11 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.08 (s, 1H), 7.63 (dd, J = 10.4, 6.5 Hz, 2H), 7.46 (d, J =4.5 Hz, 2H), 4.72 (d, J = 6.2 Hz, 2H), 4.38 (d, J = 6.2 Hz, 2H), 3.47 (s, 3H), 1.60 (s, 3H).

Example 78 [Chemical Formula 175] Compound 78

Synthetic route [Chemical formula 176]

steps 1 : compound 78 Synthesis

The operation steps were the same as the synthesis of compound 77, except that 77-h was replaced by 78-a (39.2 mg, 0.31 mmol) to obtain compound 78 (12 mg, 0.002 mmol) as a yellow solid. MS m/z(ESI): 445.11 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 8.80 (d, J = 6.8 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.43 (d, J =4.8 Hz, 2H), 5.05 (d, J = 5.5 Hz, 1H), 4.26 (q, J = 5.8 Hz, 2H), 3.46 (s, 3H), 2.23 (ddd, J = 11.6, 6.8, 4.5Hz, 2H), 2.13 (ddd , J = 12.6, 8.0, 5.2 Hz, 2H). Example 79

[Chemical formula 177] Compound 79

Synthetic route [Chemical formula 178]

steps 1 : compound 79 Synthesis

The operation steps were the same as the synthesis of compound 50, except that 50-d was replaced by 79-a (44.6 mg, 0.20 mmol) to obtain compound 79 (14.5 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 521.19 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 9.61 (s, 1H), 8.37 (s, 1H), 8.19 (dd, J=5.8, 2.7 Hz, 1H), 7.97 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.76 (s, 1H), 7.55 (t, J=9.1Hz,1H), 7.47 (s, 1H), 3.47 (s, 3H), 3.27(d, J = 12.3 Hz, 4H).

Example 80 [Chemical Formula 179] Compound 80

Synthetic route [Chemical formula 180]

steps 1 : compound 80 Synthesis

The operation steps were the same as the synthesis of compound 20, except that 20-d was replaced by 80-a (39.2 mg, 0.31 mmol) to obtain compound 80 (16.9 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 425.22 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 9.09 (s, 1H), 7.65 – 7.56 (m, 2H), 7.34 (d, J = 6.7 Hz, 2H), 4.68 (d, J = 6.3 Hz, 2H), 4.38 (d, J = 6.3 Hz, 2H), 3.41 (s, 3H), 2.20 (s, 3H), 1.59 (s, 3H).

Example 81 [Chemical Formula 181] Compound 81

Synthetic route [Chemical formula 182]

steps 1 : compound 81 Synthesis

The operation steps were the same as the synthesis of compound 20, except that 20-d was replaced by 81-a (39.2 mg, 0.31 mmol) to obtain compound 81 (12 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 425.22 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.84 (d, J = 7.0 Hz, 1H), 7.60 (dd, J = 10.4, 6.5 Hz, 2H), 7.30 (d, J = 6.9 Hz, 2H), 5.05 (d, J = 5.5 Hz, 1H), 4.28 (h, J = 6.4 Hz, 2H), 3.40 (s, 3H), 2.25 – 2.10 (m,7H).

Example 82 [Chemical Formula 183] Compound 82

Synthetic route [Chemical formula 184]

steps 1 : compound 82 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 82-a (8.5 mg, 0.07 mmol) to obtain compound 82 (5 mg, 0.01 mmol) as a yellow solid. MS m/z(ESI): 409.19 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.35 (s, 1H), 9.60 (s, 1H), 8.20 (ddd, J = 5.9, 2.7, 1.3 Hz, 1H), 7.97 (ddt, J = 9.4 , 4.7, 2.2 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.38 (d, J = 5.9 Hz, 2H), 3.41 (s, 3H), 2.14 (s, 3H), 1.63 – 1.56 (m, 2H), 1.25 – 1.18 (m, 2H).

Example 83 [Chemical Formula 185] Compound 83

Synthetic route [Chemical formula 186]

steps 1 : compound 83 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 83-a (35.1 mg, 0.29 mmol) to obtain compound 83 (27.5 mg, 0.06 mmol) as a yellow solid. MS m/z(ESI): 412.25 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.59 (d, J = 8.3 Hz, 1H), 8.27 – 8.16 (m, 1H), 7.96 (ddt, J = 9.6, 4.9, 2.3Hz, 1H), 7.53 (t , J = 9.1 Hz, 1H), 7.30 (d, J = 7.1 Hz, 1H), 3.41 (s, 3H), 3.29 (d, J = 6.9 Hz, 1H), 2.21 (s,3H), 1.18 (d , J = 6.7 Hz, 3H), 0.92 (dtd, J = 13.1, 8.3, 4.7 Hz, 1H), 0.41 (dtd, J = 16.9, 8.6, 4.4 Hz, 2H), 0.26 (ddt, J = 26.2, 9.0 , 4.3 Hz, 2H).

Example 84 [Chemical Formula 187] Compound 84

Synthetic route [Chemical formula 188]

steps 1 : compound 84 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 84-a (12.6 mg, 0.15 mmol) to obtain compound 84 (15 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 411.16 [M+H] ⁺ .

1H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 9.26 (s, 1H), 8.21 (dd,J = 7.3, 4.1 Hz, 1H), 7.98 (ddd,J = 9.1, 4.7, 2.4 Hz, 1H), 7.54 (t,J = 9.1 Hz, 1H), 7.35 (d,J = 6.0 Hz, 1H), 3.42 (s, 3H), 2.19 (s, 3H), 1.66 (s, 6H) .

Example 85 [Chemical Formula 189] Compound 85

Synthetic route [Chemical formula 190]

steps 1 : compound 85 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 85-a (30.5 mg, 0.29 mmol) to obtain compound 85 (18.3 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 396.23 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.18 (dd, J = 5.9, 2.6 Hz, 1H), 7.96 (ddt, J = 9.3, 4.6, 2.1Hz, 1H), 7.53 (t , J = 9.1 Hz, 1H), 7.31 (d, J = 6.6 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.41 (s, 3H), 3.22 (d, J =2.3 Hz, 1H), 2.16 (s, 3H), 1.36 (d, J = 6.9 Hz, 3H).

Example 86 [Chemical Formula 191] Compound 86

Synthetic route [Chemical formula 192]

steps 1 : compound 86 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 86-a (5.1 mg, 0.06 mmol) to obtain 10 mg of light yellow product compound 86. MS m/z(ESI): 407.15 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.16 (d, J = 23.3 Hz, 1H), 9.16 – 8.98 (m, 1H), 8.27 (d, J = 39.1 Hz, 1H), 7.83 (ddd, J = 14.7 , 8.8, 6.8 Hz, 1H), 7.46 – 7.19 (m, 3H), 4.65 (d, J = 6.3 Hz, 2H), 4.36 (d, J = 6.3 Hz, 2H), 3.39 (s, 3H), 2.18 (s, 3H), 1.56 (s, 3H).

Example 87 [Chemical Formula 193] Compound 87

Synthetic route [Chemical formula 194]

steps 1 : compound 87 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 87-a (39.2 mg, 0.29 mmol) to obtain compound 87 (14.6 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 426.25 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.18 (dd, J =5.8, 2.7 Hz, 1H), 7.96 (ddt, J = 9.3 , 4.8, 2.3 Hz, 1H), 7.53 (t, J = 9.1 Hz, 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, 6.7 Hz, 4H), 1.00 (d, J = 6.6 Hz, 3H). Example 88 [Chemical Formula 195] Compound 88

Synthetic route [Chemical formula 196]

steps 1 : compound 88 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 88-a (50.8 mg, 0.29 mmol) to obtain compound 88 (13.3 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 466.24 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 9.38 (d, J = 9.0 Hz, 1H), 8.19 (ddd, J = 5.8, 2.7, 1.4 Hz, 1H), 7.97 (ddt, J = 9.4, 4.8, 2.3 Hz , 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.35 (d, J = 6.4 Hz, 1H), 4.04 (q, J = 7.8 Hz, 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, 4.6 Hz, 3H), 0.38 – 0.29 (m,1H).

Example 89 [Chemical Formula 197] Compound 89

Synthetic route [Chemical formula 198]

steps 1 : compound 89-b Synthesis

The operation steps were the same as the synthesis of compound 1-d, except that 1-c was replaced by 89-a (2.99 g, 23.9 mmol) to obtain reddish-brown solid compound 89-b (1.6 g, 6.50 mmol). MS m/z(ESI): 247.16 [M+H] ⁺ .

steps 2 : compound 89-c Synthesis

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

steps 3 : compound 89-d Synthesis

The operation steps were the same as the synthesis of compound 2-g, except that 2-f was replaced by 89-c (1.1 g, 3.17 mmol) to obtain reddish-brown solid compound 89-d (1.3 g, 2.03 mmol). MS m/z(ESI): 642.21 [M+H] ⁺ .

steps 4 : compound 89-e Synthesis

The operation steps were the same as the synthesis of compound 2, except that 2-g was replaced by 89-d (1.3 g, 2.03mmol) to obtain compound 89-e (0.16 g, 0.44mmol) as a yellow solid. MS m/z(ESI): 362.22 [M+H] ⁺ .

steps 5 : compound 89-f Synthesis

The operation steps were the same as the synthesis of compound 8-c, except that 8-b was replaced by 89-e (0.16 g, 0.44mmol) to obtain compound 89-f (0.10 g, 0.30mmol) as a yellow solid. MS m/z(ESI): 334.29 [M+H] ⁺ .

steps 6 : compound 89 Synthesis

The operation steps are the same as the synthesis of compound 8, except that 8-c is replaced by 89-f (30 mg, 0.10 mmol), and 8-d is replaced by 2-a to obtain compound 89 (2.4 mg, 0.05 mmol) as a yellow solid. MS m/z(ESI): 429.16 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.32 (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 = 9.2 Hz, 1H), 4.71 (q, J = 7.3 Hz, 1H), 3.40 (s, 3H), 2.23 (d, J = 1.9 Hz, 3H), 2.12 (s,3H), 1.31 (d , J = 7.0 Hz, 3H). Example 90 [Chemical Formula 199] Compound 90

Synthetic route [Chemical formula 200]

steps 1 : compound 90-b Synthesis

Add 90-a (13 mL, 116.35 mmol) into a three-necked flask, add dry tetrahydrofuran (140 mL), protect with nitrogen, stir at −78°C for 10 minutes, add methyl- d3 -magnesium iodide (65 mL ₎ , 1M in Et2O) was slowly dropped into it, and after stirring for 2 hours at −78°C, 1M HCl aqueous solution (35 mL) was slowly added to quench, the reaction was raised to room temperature, saturated brine (100 mL) was added, and the liquids were separated. After the volume of the upper organic phase was concentrated to one third, it was used directly in the next step.

steps 2 : compound 90-c Synthesis

Dissolve 17-b (7 g, 32.11 mmol) in a mixed solvent of toluene (160 mL) and water (40 mL), add 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), under nitrogen protection, heated to 87°C and stirred overnight. Add saturated brine (200 mL), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform column chromatography (PE/EA = 9/1) to obtain light yellow oily liquid 90-c (3.6 g, 23.05 mmol). MS m/z (ESI): 157.14 [M+H] ⁺ .

steps 3 : compound 90-d Synthesis

Add 90-c (3.6 g, 23.05 mmol) and 4-b (3.8 g, 27.66 mmol) into a three-necked flask, add tetrahydrofuran (80 mL) to dissolve, and stir in an ice-water bath for five minutes under nitrogen protection. Silica-based lithium amide (69.14 mL, 69.14 mmol) was slowly dropped into it. After the dropwise addition was completed, after reacting at room temperature for 2 hours, the reaction solution was quenched with ice water (100 mL), and saturated brine (100 mL) was added. and ethyl acetate (100 mL), separate the layers, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then add a small amount of ethyl acetate to the obtained solid. Beat, filter, and wash with a small amount of ethyl acetate to obtain an off-white solid 90-d (4 g, 15.37 mmol). MS m/z (ESI): 261.18 [M+H] ⁺ .

steps 4 : compound 90-e Synthesis

Add 90-d (4 g, 15.37 mmol) into the reaction flask, add dichloromethane (50 mL), slowly add 2-b (8.60 mL, 76.83 mmol) under an ice water bath, and add aluminum trichloride (14.3 g, 107.57 mmol) was added in batches, under nitrogen protection, after reacting at room temperature for 4 hours, the reaction solution was slowly poured into ice water (100 mL), a large amount of white solid precipitated, filtered, the white filter cake was evaporated to dryness, and the filtrate was The liquids were separated, and the organic phase was washed with saturated brine (200 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. After the organic phase was concentrated under reduced pressure, the filter cakes were combined to obtain an off-white solid 90-e (5 g, 13.87 mmol). . MS m/z (ESI): 361.18 [M+H] ⁺ .

steps 5 : compound 90-f Synthesis

Add 90-e (3.5 g, 9.71 mmol) and NFSI (61.2 g, 194.23 mmol) into the reaction flask, add ethyl acetate (50 mL), then add TEMPO (15.2 g, 97.11 mmol), and raise the temperature under nitrogen protection. After reacting at 50°C for 18 hours, concentrate and purify through a C18 column. The eluate ratio is: 80% (acetonitrile): 20% (ultrapure water [0.005%/L formic acid]). Collect the purified product and concentrate under reduced pressure. , obtaining orange solid 90-f (6.36 g, 9.70 mmol). MS m/z (ESI): 656.25 [M+H] ⁺ .

steps 6 : compound 90-g Synthesis

Add 90-f (6.36 g, 9.70 mmol) into the reaction flask, dissolve it in 1,2-dichloroethane (60 mL), add trifluoromethanesulfonic acid (5.14 mL, 58.20 mmol), and raise the temperature to 80° C, stir for 20 minutes, concentrate at room temperature to obtain a black oily crude product, add ethyl acetate (100 mL) to dissolve, add saturated sodium bicarbonate aqueous solution (30 mL) in an ice-water bath, separate the layers, and add saturated salt to the organic phase. After washing with water (100 mL), spin to dryness and purify through a C18 column. The ratio of the eluate is: 60% (acetonitrile): 40% (ultrapure water [0.005%/L formic acid]). The purified product is collected and concentrated under reduced pressure. , 90-g (1.1 g, 2.93 mmol) of orange solid was obtained. MS m/z(ESI): 376.25 [M+H] ⁺ .

steps 7 : compound 90-h Synthesis

Dissolve 90-g (200 mg, 0.53 mmol) in a mixed solvent of ethanol (9 mL) and water (3 mL), add sodium hydroxide (128 mg, 3.20 mmol) under an ice-water bath, and react at room temperature for about 1 hours. LCMS monitors that after the raw materials are consumed, the pH is adjusted to about 5, concentrated, and solids precipitate, filtered, and the filter cake is evaporated to dryness to obtain a yellow-brown solid for 90-h (150 mg, 0.43 mmol). MS m/z (ESI): 348.24 [M+H] ⁺ .

steps 8 : compound 90 Synthesis

Add 90-h (60 mg, 0.12 mmol) and 2-a (21.7 mg, 0.15 mmol) into the reaction flask, add N , N -dimethylformamide (2 mL) to dissolve, then add N , N- Diisopropylethylamine (0.06 mL, 0.36 mmol) was stirred in an ice-water bath for 1 minute, and then HATU (55.2 mg, 0.15 mmol) was added and stirred in an ice-water bath for 20 minutes. The reaction solution was directly purified through a C18 column. The eluate ratio was: 50% (acetonitrile): 50% (ultrapure water [0.005%/L formic acid]). The purified product was collected and freeze-dried to obtain a yellow solid compound 90 (25 mg ,0.06 mmol). MS m/z (ESI): 443.12 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 9.24 (d, J = 8.8 Hz, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 7.96 (ddd, J = 9.2 , 4.9, 2.7 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.36 (s, 2H), 4.71 (h, J = 7.5 Hz, 1H), 3.42 (s, 3H), 1.31 (d , J = 7.0 Hz, 3H).

Example 91 [Chemical Formula 201] Compound 91

Synthetic route [Chemical formula 202]

Step: Compound 91 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 91-a (10.02 mg, 0.06 mmol) to obtain 13 mg of the pale yellow product compound 91. MS m/z(ESI): 494.21 [M+H] ⁺ .

1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.17 (dd,J = 5.7, 2.6 Hz, 1H), 8.09 (s, 1H), 8.00 – 7.90 (m, 1H), 7.50 (t, J = 9.1 Hz, 1H), 7.22 (d,J = 7.2 Hz, 2H), 4.45 (d,J = 55.4 Hz, 1H), 3.39 (s, 3H), 2.21 (s, 3H), 2.15 (s, 2H), 1.88 (d,J = 10.0 Hz, 6H), 1.60 – 1.39 (m, 6H).

Example 92 [Chemical Formula 203] Compound 92

Synthetic route [Chemical formula 204]

steps 1 : compound 92 Synthesis

The operating steps were the same as the synthesis of compound 77, except that 77-h was replaced by 2-a (31.7 g, 0.21 mmol) to obtain compound 92 (20.3 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 471.15 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.22 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 10.3, 6.4 Hz, 2H), 7.48 (s, 2H), 4.69 (h, J = 7.6 Hz, 1H), 3.47 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H).

Example 93 [Chemical Formula 205] Compound 93

Synthetic route [Chemical formula 206]

Step: Compound 93 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 93-a (7.84 mg, 0.07 mmol) to obtain 15 mg of the pale yellow product compound 93. MS m/z(ESI): 439.13 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 11.04 (s, 1H), 10.32 (s, 1H), 8.51 (s, 1H), 8.28 – 8.19 (m, 1H), 8.16 (dd, J = 5.7, 2.6 Hz, 1H), 7.98 – 7.88 (m, 1H), 7.50 (t, J = 9.1 Hz, 1H), 7.42 (d, J = 5.5 Hz, 2H), 7.22 (dd, J = 8.8, 3.1 Hz, 1H), 3.42 (s, 3H), 2.12 (s, 3H).

Example 94 [Chemical Formula 207] Compound 94

Synthetic route [Chemical formula 208]

steps 1 : compound 94 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 94-a (8.1 mg, 0.09 mmol) to obtain compound 94 (15 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 416.13 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 8.01-7.91 (m, 2H), 7.53 (t, J = 9.1 Hz, 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).

Example 95 [Chemical Formula 209] Compound 95

Synthetic route [Chemical formula 210]

steps 1 : compound 95 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 95-a (12.4 mg, 0.09 mmol) to obtain compound 95 (15 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 428.11 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.27 (s, 1H), 8.42 (s, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 8.02-7.93 (m, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.29 (s, 2H), 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).

Example 96 [Chemical Formula 211] Compound 96

Synthetic route [Chemical formula 212]

steps 1 : compound 96 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 96-a (10.5 mg, 0.09 mmol) to obtain compound 96 (12 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 442.23 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.23-8.17 (m, 1H), 8.08 (s, 1H), 8.01-7.93 (m, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.27 (d, J = 7.4 Hz, 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).

Example 97 [Chemical Formula 213] Compound 97

Synthetic route [Chemical formula 214]

steps 1 : compound 97 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 97-a (15.2 mg, 0.12 mmol) to obtain compound 97 (20.5 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 458.16 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 8.06 (s, 1H), 7.97 (ddd, J = 9.3, 4.9 , 2.7 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.27 (d, J = 7.2 Hz, 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 = 13.4 Hz, 2H), 1.68 (td, J = 12.4, 4.6 Hz, 2H).

Example 98 [Chemical Formula 215] Compound 98

Synthetic route [Chemical formula 216]

steps 1 : compound 98 Synthesis

The operation steps were the same as the synthesis of compound 50, except that 50-d was replaced by 3-c (5.50 mg, 0.10 mmol) to obtain 10 mg of the pale yellow product compound 98. MS m/z(ESI): 402.07 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 7.97 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.55 (t, J = 9.1 Hz, 1H ), 7.43 (d, J = 4.2 Hz, 1H), 3.99 (dd, J = 6.2, 2.6 Hz, 2H), 3.47 (s, 3H), 3.15 (t, J = 2.5 Hz, 1H), 2.86 (s , 3H).

Example 99 [Chemical Formula 217] Compound 99

Synthetic route [Chemical formula 218]

steps 1 : compound 99 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 99-a (18 mg, 0.17 mmol) to obtain compound 99 (13 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 430.31 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.29 (s, 1H), 8.44 (t, J = 6.2 Hz, 1H), 8.24 – 8.09 (m, 1H), 8.02 – 7.88 (m, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.39 – 7.27 (m, 2H), 4.56 (t, J = 5.7 Hz, 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).

Example 100 [Chemical Formula 219] Compound 100

Synthetic route [Chemical formula 220]

steps 1 : compound 100 Synthesis

The operation steps were the same as the synthesis of compound 89, except that 2-a was replaced by 3-c (5.50 mg, 0.10 mmol) to obtain 12 mg of the pale yellow product compound 100. MS m/z(ESI): 371.14 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 7.62 (d, J = 7.1 Hz, 1H), 7.49 (dd, J = 5.8, 3.3 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.10 ( t, J = 9.2 Hz, 1H), 3.98 (q, J = 2.8 Hz, 2H), 3.40 (s, 3H), 3.15 (t, J = 2.5 Hz, 1H), 2.23 (d, J = 1.9 Hz, 3H), 2.13 (s, 3H).

Example 101 [Chemical Formula 221] Compound 101

Synthetic route [Chemical formula 222]

steps 1 : compound 101 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 101-a (28.4 mg, 0.22 mmol) to obtain compound 101 (11 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 421.40 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.96 (s, 1H), 10.32 (s, 1H), 8.86 (d, J = 2.3 Hz, 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, 1.5 Hz, 1H), 8.00 – 7.91 (m, 1H), 7.53 (t, J = 9.2 Hz, 1H) , 7.48 – 7.33 (m, 2H), 3.44 (s, 3H), 2.14 (s, 3H).

Example 102 [Chemical Formula 223] Compound 102

Synthetic route [Chemical formula 224]

steps 1 : compound 102-a Synthesis

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

steps 2 : compound 102-b Synthesis

The operation steps were the same as the synthesis of compound 90-e, except that 90-d was replaced by 102-a (2 g, 7.9 mmol) to obtain compound 102-b (2.7 g, 7.64 mmol) as a white solid. MS m/z(ESI): 354.14 [M+H] ⁺ .

steps 3 : compound 102-c Synthesis

The operation steps were the same as the synthesis of compound 90-f, except that 90-e was replaced by 102-b (1 g, 2.83 mmol) to obtain compound 102-c (1.8 g, 2.77 mmol) as a white solid. MS m/z(ESI): 649.28 [M+H] ⁺ .

steps 4 : compound 102-d Synthesis

The operation steps were the same as the synthesis of compound 90-g, except that 90-f was replaced by 102-c (1.8 g, 2.77 mmol) to obtain compound 102-d (0.5 g, 1.36 mmol) as a white solid. MS m/z(ESI): 369.46 [M+H] ⁺ .

steps 5 : compound 102-e Synthesis

The operation steps were the same as the synthesis of compound 90-h, except that 90-g was replaced by 102-d (100 mg, 0.27 mmol) to obtain compound 102-e (50 mg, 0.15 mmol) as a white solid. MS m/z(ESI): 341.11 [M+H] ⁺ .

steps 6 : compound 102 Synthesis

The operation steps were the same as the synthesis of compound 90, except that 90-h was replaced by 102-e (50 mg, 0.15 mmol) to obtain compound 102 (50 mg, 0.15 mmol) as a white solid. MS m/z(ESI): 436.13 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 9.23 (d, J = 8.7 Hz, 1H), 7.90 – 7.81 (m, 1H), 7.47 – 7.38 (m, 2H), 7.35 (s , 2H), 4.71 (h, J = 7.6 Hz, 1H), 3.41 (s, 3H), 1.31 (d, J = 7.1 Hz, 3H).

Example 103 [Chemical Formula 225] Compound 103

Synthetic route [Chemical formula 226]

Step: Compound 103 Synthesis

The operation steps were the same as the synthesis of compound 8, except that 8-d was replaced by 51-a (12.18 mg, 0.07 mmol) to obtain 16 mg of the pale yellow product compound 103. MS m/z(ESI): 494.14 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.57 (d,J = 34.1 Hz, 1H), 7.86 – 7.79 (m, 1H), 7.75 (s, 1H), 7.39 (dd,J = 8.5, 5.6 Hz, 2H), 7.34 (s, 2H), 3.43 (s, 3H), 3.26 (s, 3H), 2.02 (s, 3H).

Example 104 [Chemical Formula 227] Compound 104

Synthetic route [Chemical formula 228]

steps 1 : compound 104 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 104-a (9.03 mg, 0.07 mmol) to obtain 16 mg of the pale yellow product compound 104. MS m/z(ESI): 456.12 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.22 (d, J = 8.9 Hz, 1H), 8.17 (dd, J = 5.7, 2.5 Hz, 1H), 8.02 – 7.87 (m, 1H) , 7.51 (t, J = 9.1 Hz, 1H), 7.35 (s, 2H), 4.71 – 4.50 (m, 1H), 3.72 (dd, J = 4.8 Hz, 1H), 3.66-3.62 (m, 1H), 2.14 (s, 3H).

Example 105 [Chemical Formula 229] Compound 105

Synthetic route [Chemical formula 230]

steps 1 : compound 105-b Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 105-a (30.0 mg, 0.17 mmol) to obtain 59 mg of light yellow product compound 105-b. MS m/z(ESI): 499.20 [M+H] ⁺ .

steps 2 : compound 105 Synthesis

Compound 105-b (59 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. Stir at room temperature for 1 hour. Adjust pH=5~6 with saturated sodium carbonate solution in an ice-water bath. Extract three times with a mixed solvent of DCM/MeOH = 10/1, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was preparatively purified to obtain 25 mg of light yellow solid compound 105. MS m/z(ESI): 399.15 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 10.33 (s, 1H), 9.27 (d, J = 7.0 Hz, 1H), 8.17 (dd, J = 5.8, 2.6 Hz, 1H), 7.94 (m, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.34 (s, 2H), 4.65 (d, J = 7.4 Hz, 1H), 3.88 – 3.84 (m, 2H), 3.71 (s, 2H), 3.39 (s, 3H), 2.11 (s, 3H).

Example 106 [Chemical Formula 231] Compound 106

Synthetic route [Chemical formula 232]

steps 1 : compound 106 Synthesis

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

¹ HNMR (400 MHz, DMSO) δ 10.29 (s, 1H), 9.25 (d,J = 6.7 Hz, 1H), 8.17 (dd,J = 5.8, 2.6 Hz, 1H), 7.94 (m, 1H), 7.51 (t,J = 9.1 Hz, 1H), 7.34 (s, 2H), 4.58 – 4.47 (m, 1H), 4.40 (t,J = 8.2 Hz, 1H), 4.10 (t,J = 8.8 Hz, 1H) , 3.98 (dd,J = 8.5, 5.3 Hz, 1H), 3.75 (dd,J = 9.7, 5.4 Hz, 1H), 3.39 (s, 3H), 2.13 (s, 3H), 1.75 (s, 3H).

Example 107 [Chemical Formula 233] Compound 107

Synthetic route [Chemical formula 234]

steps 1 : compound 107 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 110-d (11.8 mg, 0.14 mmol) to obtain compound 107 (18 mg, 0.04 mmol) as a yellow solid. MS m/z(ESI): 412.15 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.34 (s, 1H), 8.98 (d, J = 8.2 Hz, 1H), 8.19 (dd, J = 5.8, 2.6 Hz, 1H), 7.96 (m J = 9.0, 4.8, 2.7 Hz, 1H), 7.53 (t, J = 9.2 Hz, 1H), 7.33 (s, 2H), 5.16 (s, 1H), 4.63 (dd, J =12.8, 6.1 Hz, 1H) , 3.55 (dd, J = 13.6, 8.3 Hz, 2H), 3.41 (s, 3H), 3.22 (d, J = 2.3 Hz, 1H), 2.18 (s, 3H).

Example 108 [Chemical Formula 235] Compound 108

Synthetic route [Chemical formula 236]

steps 1 : compound 108 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 108-a (7.7 mg, 0.07 mmol) to obtain compound 108 (15 mg, 0.03 mmol) as a yellow solid. MS m/z(ESI): 438.17 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 9.04 (t, J = 5.6 Hz, 1H), 8.18 (dd, J = 5.8, 2.6 Hz, 1H), 7.95 (m, J = 9.1, 4.8, 2.7 Hz, 1H), 7.53 (t, J = 9.2 Hz, 1H), 7.32 (s, 2H), 7.08 (s, 1H), 6.80(d, J = 1.0 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 3.68 (s, 3H), 3.40 (s, 3H), 2.07 (s, 3H).

Example 109 [Chemical Formula 237] Compound 109

Synthetic route [Chemical formula 238]

steps 1 : compound 109 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 109-a (13.7 mg, 0.24 mmol) to obtain compound 109 (7 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 384.13 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.31 (s, 1H), 8.64 (d, J = 4.4 Hz, 1H), 8.19 (dd, J = 5.7, 2.6 Hz, 1H), 8.04 – 7.86 ( m, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.32 (s, 2H), 3.40 (s, 3H), 2.75 (m, J = 7.2, 3.7 Hz, 1H), 2.15 (s, 3H ), 0.72 – 0.67 (m, 2H), 0.54 – 0.46 (m, 2H).

Example 110 [Chemical Formula 239] Compound 110

Synthetic route [Chemical formula 240]

steps 1 : compound 110-c Synthesis

A 40 mL vial was charged with 110-a (2 g, 8.72 mmol), 110-b (2 g, 10.47 mmol), K ₂ CO ₃ (3.6 g, 26.17 mmol), and methanol (50 mL). The resulting solution was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and diluted with ethyl acetate (3 × 50 mL). The mixture was washed with brine (50 mL) and water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Silica gel column purification and concentration under reduced pressure gave 1.6 g of 110-c as a yellow oil.

steps 2 : compound 110-d Synthesis

A solution of 110-c (1.6 g, 7.10 mmol), 4 M hydrochloric acid in 1,4-bistriol (10 mL), and ethanol (20 mL) was stirred at 60°C overnight. The mixture was concentrated under reduced pressure to obtain 780 mg of a tan product, compound 110-d.

steps 3 : compound 110 Synthesis

The operation steps were the same as the synthesis of compound 89, except that 2-a was replaced by 110-d (8.50 mg, 0.10 mmol) to obtain 15 mg of the pale yellow product compound 110. MS m/z(ESI): 401.15 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 9.91 (d,J = 35.2 Hz, 1H), 8.89 (t,J = 16.5 Hz, 1H), 7.64 – 7.55 (m, 1H), 7.53 – 7.40 (m, 1H) , 7.27 (s, 2H), 7.12 – 7.00 (m, 1H), 4.65 – 4.54 (m, 1H), 3.52 (dd,J = 6.1, 4.2 Hz, 2H), 3.41 (s, 3H), 3.19 (d ,J = 2.1 Hz, 1H), 2.21 (s, 3H), 2.13 (s, 3H).

Example 111 [Chemical Formula 241] Compound 111

Synthetic route [Chemical formula 242]

steps 1 : compound 111 Synthesis

The operating steps were the same as the synthesis of compound 9, except that 9-e was replaced by 111-a (6.78 mg, 0.07 mmol) to obtain 13 mg of the pale yellow product compound 111. MS m/z(ESI): 424.13 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 10.32 (d, J = 19.9 Hz, 1H), 9.62 (d, J = 20.2 Hz, 1H), 8.16 (dt, J = 13.9, 6.9 Hz, 1H), 7.99 – 7.90 (m, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.37 (s, 2H), 4.71 (dd, J = 21.8, 6.5 Hz, 4H), 3.61 (s, 1H), 3.40 (s, 3H), 2.18 (s, 3H).

Example 112 [Chemical Formula 243] Compound 112

Synthetic route [Chemical formula 244]

steps 1 : compound 112 Synthesis

Add compound 34 (82 mg, 0.21 mmol), TMS-N ₃ (24.8 mg, 0.21 mmol), methanol (2 mL), acetonitrile (2 mL), water (1 mL), and sulfuric acid pentahydrate into the two-neck flask. Copper (8.1 mg, 0.03 mmol), sodium ascorbate (10.6 mg, 0.05 mmol), potassium carbonate (29.7 mg, 0.21 mmol), protected by nitrogen, then stirred at room temperature for 2 hours, quenched the reaction solution with water, and used acetic acid Extract the aqueous phase (3 × 50 mL) with ethyl ester, combine the organic layers, add saturated brine (20 mL) to wash, and then dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify through a C18 column. Eluent ratio : 70% (acetonitrile): 30% (ultrapure water [0.005%/L formic acid]) – 50% (acetonitrile): 50% (ultrapure water [0.005%/L formic acid]), collect the purified products, and concentrate under reduced pressure , obtaining about 13 mg of compound 112 as a yellow solid. MS m/z(ESI): 425.10 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.30 (s, 1H), 9.09 (t, J = 5.8 Hz, 1H), 8.37 (s, 1H), 8.17 (dd, J = 5.8, 2.6 Hz, 1H), 8.07 – 7.87 (m, 1H), 7.71 (s, 1H), 7.52 (t, J = 9.1 Hz, 1H), 7.33 (s, 2H), 4.46 (d, J = 5.5 Hz, 2H), 3.39 (s, 3H), 2.06 (s, 3H).

Example 113 [Chemical Formula 245] Compound 113

Synthetic route [Chemical formula 246]

steps 1 : compound 113 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 113-a (22.9 mg, 0.17 mmol) to obtain compound 113 (11 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 458.21 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 8.72 (t, J = 5.9 Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.53 (t, J = 9.2 Hz, 1H), 7.34 (s, 2H), 4.17 (t, J = 6.0 Hz, 1H), 3.99 (dd, J = 8.4 , 6.2 Hz, 1H), 3.68 (dd, J = 8.4, 5.7 Hz, 1H), 3.39 (s, 3H), 3.28 (dd, J = 11.4, 5.9 Hz, 2H), 2.15 (s, 3H), 1.35 (s, 3H), 1.26 (s, 3H).

Example 114 [Chemical Formula 247] Compound 114

Synthetic route [Chemical formula 248]

steps 1 : compound 114 Synthesis

Add compound 113 (4 mg, 0.01 mmol) into a single-neck bottle, add 1N dilute hydrochloric acid (0.5 mL), and then stir at room temperature for 10 min. The reaction solution is directly purified through a C18 column. The eluate ratio is: 70% (Acetonitrile): 30% (Ultrapure water [0.005%/L formic acid]) – 50% (Acetonitrile): 50% (Ultrapure water [0.005%/L formic acid]). Collect the purified products and concentrate under reduced pressure to obtain approximately 3 mg of compound 114 as a yellow solid. MS m/z(ESI): 418.21 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.31 (s, 1H), 8.47 (t, J = 5.7 Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.96 (ddd, J = 8.6, 4.8, 2.7 Hz, 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 = 5.9 Hz, 2H), 3.40 (s, 3H), 3.30 (d, J = 9.3 Hz, 2H), 3.15 – 3.07 (m, 1H), 2.18 (s, 3H).

Example 115 [Chemical Formula 249] Compound 115

Synthetic route [Chemical formula 250]

steps 1 : compound 115 Synthesis

The operation steps were the same as the synthesis of compound 9, except that 9-e was replaced by 115-a (12.0 mg, 0.09 mmol) to obtain compound 115 (8 mg, 0.02 mmol) as a yellow solid. MS m/z(ESI): 458.17 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 8.42 (t, J = 6.1 Hz, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 8.00-7.91 ( m, 1H), 7.53 (t, J = 9.1 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 3.64-3.58 (m, 4H), 3.41 (s, 3H), 3.22 (d, J = 6.0 Hz, 2H), 2.18 (s, 3H), 1.63-1.54 (m, 2H), 1.44-1.37 (m, 2H).

Comparative Example Preparation of Compound A (Compound A ) [Chemical Formula 251] Compound A

Synthetic route [Chemical formula 252]

steps 1 : compound 116-b Synthesis

The operation steps are the same as the synthesis of compound 1-d, except that 1-b is replaced by 116-a (3 g, 16.56 mmol), 1-c is replaced by 4-b (3.2 g, 23.18 mmol), and 116-b (2 g, 23.18 mmol) is obtained. 7.37 mmol). MS m/z(ESI): 272.28 [M+H] ⁺ .

steps 2 : compound 116-c Synthesis

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

steps 3 : compound 116-d Synthesis

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

steps 4 : compound A Synthesis

The operation steps are the same as the synthesis of compound 9, except that 9-d is replaced by 116-d (230 mg, 0.67 mmol) and 9-e is replaced by 2-a (119.8 mg, 0.80 mmol) to obtain a yellow solid compound A (90 mg, 0.21 mmol). MS m/z(ESI): 439.11 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.54 (s, 1H), 9.35 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 5.8, 2.7 Hz, 1H), 7.97 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 4.71 (h, J = 7.5 Hz, 1H), 3.60 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H).

Example 116 : HepG2.2.15 cells in vitro HBV Activity test

1. Compound dilution: Dilution method ① Dilution method of compound 2-21 : First use DMSO to dilute the 20 μM compound stock solution 10 times to obtain a 2 μM compound, and then use culture medium to dilute the 20 μM and 2 μM compounds 200 times to the final concentration. are 100 nM and 10 nM; dilution method of compound 22-104 and compound 110-111 : first use DMSO to dilute the 20 μM compound stock solution 10 times to obtain 2 μM and 0.2 μM compounds, and then use culture medium to dilute 20 μM, 2 μM and 0.2 μM compounds were diluted 200-fold to final concentrations of 100 nM, 10 nM, and 1 nM. Dilution method ② , compound 2 , compound 7 dilution method: first use DMSO to dilute the 20 μM compound stock solution 3 times to 8 concentration points to obtain 20 μM, 6.67 μM, 2.22 μM, 0.741 μM, 0.247 μM, 0.0823 μM, 0.0274 μM and 0.00914 μM gradient diluted compounds, and then dilute the gradient diluted compounds 200 times with culture medium to final compound 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.

2. Experimental operation: On the first day, HepG2.2.15 cells (Wuhan Institute of Virology, Chinese Academy of Sciences) (6×10 ⁴ cells/well) were seeded into a 96-well plate and cultured overnight at 37°C and 5% _CO2 . Set wells with no cells and only cell culture medium as medium control. The next day, add the culture medium containing different final concentrations of compounds diluted in step 1 to the cell plate. Dilution method ① 3 duplicate wells for each concentration, dilution method ② 2 duplicate wells for each concentration. The final concentration of DMSO in the cell culture medium was 0.5%, and the final volume in the culture wells was 200 μl. Set wells with no compound added and only a final concentration of 0.5% DMSO as DMSO controls. On the fifth day, fresh medium treated with the same treatment as described above was replaced in the compound-treated wells and control wells. On the eighth day, collect the cell supernatants in the culture wells, take some samples to detect the content of HBV DNA, and use the plasmid containing the full-length sequence of D-type HBV DNA as the standard for qPCR. The range of the standard is 10 ⁷ -10 ¹ copies/μl. HBV DNA content in all samples was determined by qPCR. After collecting the supernatant, add Cell Titer-Glo reagent to the cell culture wells and incubate at room temperature for 10 minutes. Then, a microplate reader reads the chemiluminescence values in all wells to calculate cell proliferation activity.

3. Data analysis: Use the following formula to calculate the inhibition percentage:

HBV DNA inhibition rate % = (1-DNA copy number in compound sample/DNA copy number in DMSO control) × 100%.

Cell Viability % = (Luminescence value in the compound sample – Luminescence value of the medium control) / (Luminescence value of the DMSO control – Luminescence value of the medium control)) × 100%.

For the compounds tested according to the dilution method ①, the EC ₅₀ range of the anti-HBV replication activity of the compound was obtained based on the HBV DNA inhibition rate (%); for the compounds tested according to the dilution method ②, the HBV DNA inhibition rate (%) and compound concentration were calculated using GraphPad Prism software. Four-parameter method [log(agonist) vs. response – Variable slope] fitting was used to obtain the accurate EC ₅₀ value of the compound’s anti-HBV replication activity.

Using the above experimental methods, the anti-HBV activity and corresponding cell proliferation inhibitory activity of some compounds of the present invention are as follows in Table 1. [Table 1] HepG2.2.15 HBV DNA inhibition Example Compound number Anti- HBV activity, EC ₅₀ ( nM ) Cell Viability , CC ₅₀ ( nM ) Example 2 Compound 2 <1 >100 Example 3 Compound 3 >100 >100 Example 4 Compound 4 <10 >100 Example 6 Compound 6 <10 >100 Example 7 Compound 7 <1 >100 Example 8 Compound 8 <10 >100 Example 9 Compound 9 <10 >100 Example 10 Compound 10 <10 >100 Example 11 Compound 11 <10 >100 Example 12 Compound 12 <10 >100 Example 13 Compound 13 10~100 >100 Example 14 Compound 14 <10 >100 Example 15 Compound 15 <10 >100 Example 16 Compound 16 <10 >100 Example 17 Compound 17 <10 >100 Example 18 Compound 18 <10 >100 Example 19 Compound 19 <10 >100 Example 20 Compound 20 <10 >100 Example 21 Compound 21 <10 >100 Example 22 Compound 22 <10 >100 Example 23 Compound 23 <10 >100 Example 24 Compound 24 <10 >100 Example 25 Compound 25 <10 >100 Example 26 Compound 26 <10 >100 Example 27 Compound 27 10~100 >100 Example 28 Compound 28 <10 >100 Example 29 Compound 29 <10 >100 Example 30 Compound 30 <10 >100 Example 31 Compound 31 <10 >100 Example 32 Compound 32 <10 >100 Example 33 Compound 33 <10 >100 Example 34 Compound 34 <10 >100 Example 35 Compound 35 <10 >100 Example 36 Compound 36 <10 >100 Example 37 Compound 37 <10 >100 Example 38 Compound 38 <10 >100 Example 39 Compound 39 <10 >100 Example 40 Compound 40 <10 >100 Example 41 Compound 41 <10 >100 Example 43 Compound 43 10~100 >100 Example 44 Compound 44 <10 >100 Example 45 Compound 45 10~100 >100 Example 46 Compound 46 <10 >100 Example 47 Compound 47 <10 >100 Example 48 Compound 48 1~10 >10 Example 49 Compound 49 <1 >10 Example 50 Compound 50 <1 >10 Example 51 Compound 51 <1 >10 Example 52 Compound 52 >10 >10 Example 53 Compound 53 1~10 >10 Example 54 Compound 54 <1 >10 Example 55 Compound 55 <1 >10 Example 56 Compound 56 <1 >10 Example 57 Compound 57 1~10 >10 Example 58 Compound 58 <1 >10 Example 59 Compound 59 >10 >10 Example 60 Compound 60 <10 >10 Example 61 Compound 61 <1 >10 Example 62 Compound 62 1~10 >10 Example 63 Compound 63 >10 >10 Example 64 Compound 64 >10 >10 Example 65 Compound 65 <1 >10 Example 66 Compound 66 ~1 >10 Example 67 Compound 67 >10 >10 Example 68 Compound 68 ~10 >10 Example 69 Compound 69 <1 >10 Example 70 Compound 70 <1 >10 Example 71 Compound 71 <1 >10 Example 72 Compound 72 <1 >10 Example 73 Compound 73 1~10 >10 Example 74 Compound 74 >10 >10 Example 75 Compound 75 1~10 >10 Example 76 Compound 76 1~10 >10 Example 77 Compound 77 1~10 >10 Example 78 Compound 78 1~10 >10 Example 79 Compound 79 1~10 >10 Example 80 Compound 80 <1 >10 Example 81 Compound 81 1~10 >10 Example 82 Compound 82 1~10 >10 Example 83 Compound 83 1~10 >10 Example 84 Compound 84 1~10 >10 Example 85 Compound 85 1~10 >10 Example 86 Compound 86 1~10 >10 Example 87 Compound 87 1~10 >10 Example 88 Compound 88 1~10 >10 Example 89 Compound 89 1~10 >10 Example 90 Compound 90 1~10 >10 Example 91 Compound 91 1~10 >10 Example 92 Compound 92 1~10 >10 Example 93 Compound 93 1~10 >10 Example 94 Compound 94 1~10 >10 Example 95 Compound 95 1~10 >10 Example 96 Compound 96 1~10 >10 Example 97 Compound 97 1~10 >10 Example 98 Compound 98 1~10 >10 Example 99 Compound 99 1~10 >10 Example 100 Compound 100 1~10 >10 Example 101 Compound 101 1~10 >10 Example 102 Compound 102 1~10 >10 Example 103 Compound 103 <1 >10 Example 104 Compound 104 1~10 >10 Example 110 Compound 110 1~10 >10 Example 111 Compound 111 1~10 >10

Among them, when obtaining the CC ₅₀ range of the compound in Table 1, the dilution method of the compound is method ①; when obtaining the EC ₅₀ range of the compound, except for compound 2 and compound 7, the dilution method of the other compounds is method ①, compound 2 and compound Method ② was used for the dilution of 7. The EC ₅₀ ranges of compound 2 and compound 7 were summarized by the calculated accurate EC ₅₀ values.

According to Table 1, it can be seen that the compounds of the present invention have excellent anti-HBV activity and corresponding cell proliferation inhibitory activity.

Example 117 : Human liver microsome stability test ( MMS )

Human liver microsomes (BIOIVT) were used in the experiment.

Reagent preparation:

_PBS : 0.1M _{KH2PO4 and K2HPO4} buffer, pH 7.4.

MgCl ₂ : Weigh a certain amount of MgCl ₂ and prepare a 16 mM MgCl ₂ solution with PBS.

NADPH: Weigh a certain amount of NADPH and prepare NADPH to 4 mM with 16 mM _MgCl2 solution, and the final incubation concentration is 1 mM.

Compound: Use PBS to prepare the compound to be tested and the positive compound testosterone to 4 μM, and the final incubation concentration is 1 μM.

Liver microsomes: Dilute liver microsomes to 1 mg/mL in PBS for a final incubation concentration of 0.5 mg/mL.

Experimental steps:

Add the compound to be tested or the positive compound into the test tube, then add the prepared NADPH and mix evenly. Place it in a 37°C, 220 rpm incubator for pre-incubation. After pre-incubation for 5 minutes, add liver microsomes to start the reaction.

After a certain reaction time, add a certain volume of glacial acetonitrile solution containing the internal standard tolbutamide to precipitate the protein, vortex for 5 min, then centrifuge at 4000 rpm for 10 min, and take the supernatant into a 96-well plate. Put into LC-MS/MS (Shimadzu LC-30A, AB API 4500) for analysis.

The concentration (peak area ratio) of the example compound was measured by LC-MS/MS, and the rate constant was obtained by plotting "ln (compound residual amount %)" against "incubation time" in Excel to calculate the half-life and intrinsic clearance of the drug. rate, providing a basis for predicting the clearance rate in the body.

Data analysis: CL _int = (0.693/t _1/2 , microsomes) × [Incubation fluid volume (ml)/Microsomal protein mass (mg)] × [Microsomal protein mass (mg)/Liver mass (g)] ×[Liver mass (g)/Body weight (kg)] ^[8] CL _H = CL _int × f _u × Q _h / ( CL _int × f _u + Q _h ) ^[8] where CL _int - intrinsic clearance rate (ml/min/kg) CL _H ——Hepatic clearance rate (ml/min/kg) f _u ——Plasma protein binding rate 1 Q _h ——Hepatic blood flow

Experimental results: Control compound B (structural formula is: , synthesized according to the preparation method of compound 19 in the patent document WO 2015/011281 A1) and the half-life and liver clearance rate of the compound of the present invention in the human liver microsome stability test (MMS) are shown in Table 2 below. [Table 2] Human liver microsome stability test ( MMS ) compound half life hepatic clearance T _1/2 （ min ） CLH （ ml/min/kg ） Control Compound B 16.09 17.14 Compound 2 80.92 10.12 Compound 4 67.60 11.05 Compound 7 111.28 8.49 Compound 10 64.00 11.30 Compound 12 67.40 11.10 Compound 14 66.90 11.10 Compound 16 71.60 10.80 Compound 17 73.60 10.60 Compound 20 61.50 11.50 Compound 21 51.70 12.40 Compound 28 98.30 9.12 Compound 34 137.00 7.46 Compound 44 48.10 12.80 Compound 46 50.80 12.50 Compound 48 55.30 12.10 Compound 49 57.10 11.90 Compound 51 83.10 9.99 Compound 53 60.00 11.70 Compound 54 123.00 8.00 Compound 56 67.60 11.00 Compound 59 142.90 7.27 Compound 60 144.54 7.22 Compound 62 59.60 11.70 Compound 63 65.33 11.23 Compound 65 42.50 13.40 Compound 66 52.30 12.40 Compound 70 39.80 13.70 Compound 71 43.98 13.20 Compound 75 44.54 13.14 Compound 76 75.81 10.46 Compound 77 81.41 10.09 Compound 78 135.89 7.51 Compound 79 94.45 9.33 Compound 80 86.65 9.77 Compound 82 104.86 8.79 Compound 84 43.43 13.26 Compound 85 85.60 9.83 Compound 86 122.93 8.00 Compound 89 64.97 11.26 Compound 90 65.81 11.19 Compound 92 97.23 9.18

It can be seen from Table 2 that the compounds of the present invention have a longer half-life and a longer action time in the body, which is beneficial to improving the drug efficacy.

Example 118 : Mouse tissue distribution experiment

Experimental materials and methods :

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

BALB/c female mice were orally administered (30 mg/kg). Plasma, brain, liver, heart and kidney samples were collected at different time points at 0.5, 1, 3, 5 and 8 h after administration. Collect 60 μL of whole blood from the fundus venous plexus, centrifuge at 4000 rpm for 10 minutes to obtain plasma; open the abdominal cavity and perfuse the heart with physiological saline, remove the brain, liver, heart and kidney tissues, wipe away the water with filter paper, weigh and add at a ratio of 1:2 Physiological saline, homogenized and placed in EP tubes.

Sample analysis:

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

The LC-MS/MS method was used to measure drug concentrations in plasma and tissues at different times after mice were intragastrically administered control compound A and example compounds, and relevant pharmacokinetic parameters were calculated to study the pharmacokinetics of the compounds in mice. study behavior and evaluate its pharmacokinetic characteristics.

Experimental results:

The control compound A, the distribution data of compound 4, compound 7 and compound 16 of the present invention in mouse tissues were obtained as shown in Table 3-6. [Table 3] Data on distribution of control compound A in mouse tissues : Dose route PO Plasma PO Brain PO Heart PO Liver PO Kidney Dose mg/kg 30 30 30 30 30 AUC _last h×ng/ml & h×ng/g 412 ±93 82±36 531±88 1763±339 781 ±181 AUC _Tissue /AUC _Plasma / / 0.20 1.29 4.28 1.90 [Table 4] Data on the distribution of compound 4 of the present invention in mouse tissues : Dose route PO Plasma PO Brain PO Heart PO Liver PO Kidney Dose mg/kg 30 30 30 30 30 AUC _last h×ng/ml & h×ng/g 4473 ±430 252±68 7341±331 23453 ±1260 14992 ±1147 AUC _Tissue /AUC _Plasma / / 0.06 1.64 5.24 3.35 [Table 5] Data on the distribution of compound 7 of the present invention in mouse tissues : Dose route PO Plasma PO Brain PO Heart PO Liver PO Kidney Dose mg/kg 30 30 30 30 30 AUC _last h×ng/ml & h×ng/g 2446 ±652 2585±740 9630±3527 22728 ±6707 15280 ±5951 AUC _Tissue /AUC _Plasma / / 1.06 3.94 9.29 6.25 [Table 6] Data on distribution of compound 16 of the present invention in mouse tissues Dose route PO Plasma PO Brain PO Heart PO Liver PO Kidney Dose mg/kg 30 30 30 30 30 AUC _last h×ng/ml & h×ng/g 19459 ±2283 27944 ±3730 69944 ±7735 126608 ±20554 92278 ±15229 AUC _Tissue /AUC _Plasma / / 1.44 3.59 6.50 4.74

It can be seen from Table 3-6 that compared with the control compound A, the exposure of compound 4, compound 7 and compound 16 of the present invention in the target organ liver is maintained at a high and stable level at 0-8 hours, respectively. It is 13.3 times, 12.89 times and 71.8 times that of the control compound A, indicating that the compound of the present invention can play a better role in the target organ.

Example 119 : Solubility test

Experimental method: Dissolve the compound of the present invention in DMSO and gradually dilute it into compound solutions of 5003.2 μg/ml, 2501.6 μg/ml, 1250.8 μg/ml, 625.4 μg/ml, 312.7 μg/ml, and 156.4 μg/ml; and then respectively Prepare physiological medium buffers of pH 2.0 hydrochloric acid solution and pH 6.8 phosphate buffer, and dilute compound solutions of each concentration with the above physiological medium buffer to make concentrations of 250.2 μg/ml, 125.1 μg/ml, and 62.5 μg/ml. ml, 31.3 μg/ml, 15.6 μg/ml, 7.8 μg/ml solutions, shake well; use a microplate reader (Manufacturer: TECAN Model: Spark) to measure the absorbance at a wavelength of 633nm, and compare the OD values measured for each concentration solution Compare with the OD value of the blank control physiological medium buffer to determine the solubility range of the compound of the present invention.

Experimental results: The solubility of the compound of the present invention in hydrochloric acid solution at pH 2.0 is 125.1-250.2 μg/ml, and the solubility in phosphate buffer solution at pH 6.8 is 15.6-31.3 μg/ml, indicating that the solubility of the compound of the present invention has significant advantages. It is beneficial to improve the efficacy of medicine.

Industrial applicability

The compound of the present invention has excellent anti-HBV effect and can be used as a drug for treating or preventing diseases related to this effect.

The above are only preferred embodiments of the present invention. It should be pointed out that those with ordinary knowledge in the technical field to which the present invention belongs can also make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications should also be considered as the protection scope of the present invention.

References: [1] Villain P., Gonzalez P., Almonte M., et al . European Code against Cancer 4th Edition: Infections and Cancer. Cancer Epidemiol. 2015 , 39(Suppl 1): S120-38. [2] CE Samuel. Antiviral actions of interferons. Clin. Microbiol. Rev. , 2001 , 14(4): 778-809. [3] Robert G. Gish, Bruce D. Given, Ching-Lung Lai, et al . Chronic hepatitis B : Virology, natural history, current management and a glimpse at future opportunities. Antiviral Res. , 2015 , 121: 47-58. [4] E. Spyrou, CI Smith, MG Ghany. Hepatitis B: Current Status of Therapy and Future Therapies . Gastroenterol. Clin. North Am. 2020 , 49(2): 215-238. [5] JM Berke, P. Dehertogh, et al . Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes with hepatitis B virus . [6] JM Berke, P. Dehertogh, K. Vergauwen, et al . Capsid Assembly Modulators Have a Dual Mechanism of Action in Primary Human Hepatocytes Infected with Hepatitis B Virus. Antimicrob. Agents Chemother . 2017 , 61(8): e00560 -17. [7] AM Lam, et al. Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus. Antimicrob. Agents Chemother. 2018 , 63(1): e01734-18 . [8] Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993 ; 10: 1093-1095.

Claims (26)

A compound represented by formula (I), or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer: (I) Wherein, R ₁ 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, halogen, or nitrile group; R ₂ 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, or C _2-8 alkynyl; R ₃ is selected from substituted or unsubstituted C _6-10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl ; The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the C _6-10 aryl group is selected from halogen, C _1-8 alkyl, C _1-8 Haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the 5-10 membered heteroaryl is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy group, or -CN; R ₄ is selected from substituted or unsubstituted C _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 alkynyl, , ,or ; The substituent of the C _1-10 alkyl group is selected from -H, deuterium, halogen, -OH, -COOH, -C(O)NR ^a R ^b , substituted or unsubstituted 5-6 membered heteroaryl, C _3-8 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, C _1-8 alkoxy, or C _2-8 alkynyl; the 5-6 membered heteroaryl contains 1 to 3 Heteroatom selected from N, O or S; the 5-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; -CH on the 5-6 membered heterocycloalkyl ring ₂ - optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the substituent of the 5-6 membered heteroaryl is selected from halogen, C _{1- 8} alkyl, -NH ₂ , -OH, or -CF ₃ ; the substituent of the 5-6 membered heterocycloalkyl is selected from -OH, or C _1-8 alkyl; R ^a and R ^b are each independently selected From -H, or C _1-4 alkyl; -CH ₂ - on the C _3-14 cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S( =O) ₂ -substitution; the substituent of the C _3-14 cycloalkyl group is selected from -H, deuterium, C _1-8 hydroxyalkyl group, -C(O)NH ₂ , -OH, -COOH, halogen, substitution Or unsubstituted 5-6 membered heteroaryl, -CF ₃ , C _1-8 alkyl, -NH ₂ , C _1-8 alkoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or C _2-8 alkynyl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _{1- 8} haloalkyl, or C _1-8 alkyl; -CH ₂ - on the 4-14-membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S (=O) ₂ - substitution; the 4-14-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the 4-14-membered heterocycloalkyl group is selected from C _{1- 8-} hydroxyalkyl, -CF ₃ , -OH, -COOH, C _1-8 alkyl, C _1-8 carbonyl, -S(O) ₂ CH ₃ , 4-6 membered heterocycloalkyl, 5-6 membered Heteroaryl, C _2-8 alkynyl, or halogen-substituted phenyl; the 4-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl The 5-10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 5-10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 5-10-membered heteroaryl group The substituent is selected from C _1-8 alkyl, halogen, -COOH, or -CF ₃ ; the substituent of the C _6-10 aryl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, - COOH, or -B(OH) ₂ ; R ₅ is selected from -H, deuterium, or -OH; R ₆ is selected from -H, deuterium, C _1-8 alkyl, or -NH ₂ ; m is selected from 0 or 1 ; Ring A is selected from 5-6 membered heteroaryl, or phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O or S. The compound according to claim 1, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein R ₁ is selected from -H, C _1-6 alkane base, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, halogen, or nitrile group; Preferably, R ₁ 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, or Halogen; further, R ₁ is selected from C _1-4 alkyl, cyclopropyl, C _1-4 deuterated alkyl, C _1-4 alkoxy, C _1-4 deuterated alkoxy, or halogen; Further, R ₁ is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy , butoxy, pentyloxy, hexyloxy, -F, -Cl, -Br, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, deuterated hexyl , deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated butoxy, deuterated pentyloxy, or deuterated hexyloxy; further, R ₁ is selected from methyl, methyl Oxygen, -CD ₃ , -O-CD ₃ , -F, -Cl, or -Br; Most preferably, R ₁ is selected from methyl. The compound according to claim 1 or 2, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein R ₂ 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, or C _2-6 alkynyl; Preferably, R ₂ is selected From -H, C _1-6 alkyl, C _3-4 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, or ; Further, R ₂ 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 halo Hexyl; further, R ₂ is selected from -H, C _1-4 alkyl, C _1-4 deuterated alkyl, cyclopropyl, or C _1-4 haloalkyl; most preferably, R ₂ is selected from -H , methyl, ethyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, or -CD ₃ . The compound according to any one of claims 1-3, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein: R ₃ is selected from substituted or Unsubstituted phenyl, substituted or unsubstituted pyridyl, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 8} alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; Preferably, R ₃ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN; further, R ₃ is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or ; The substituent of the phenyl group is selected from -F, -Cl, -Br, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, or -CN; the substituent of the pyridyl group Selected from -F, -Cl, -Br, or C _1-4 alkyl; further, R ₃ is selected from , , , , , , , , , , , , , , , , ,or ; Furthermore, R ₃ is selected from , , , , , , , , , , , , , , ,or ; Further, R ₃ is selected from , , , , , , , , , , , ,or ; Most preferably, R ₃ is selected from , ,or . The compound according to any one of claims 1-4, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein: R ₄ is selected from substituted or Unsubstituted C _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 alkynyl, , ,or ; The substituent of the C _1-8 alkyl group is selected from -H, deuterium, halogen, -OH, -COOH, -C(O)NR ^a R ^b , substituted or unsubstituted 5-6 membered heteroaryl, C _3-6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, C _1-6 alkoxy, or C _2-6 alkynyl; the 5-6 membered heteroaryl contains 1 to 3 Heteroatom selected from N, O or S; the 5-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; -CH on the 5-6 membered heterocycloalkyl ring ₂ - optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the substituent of the 5-6 membered heteroaryl is selected from halogen, C _{1- 6} alkyl, -NH ₂ , -OH, or -CF ₃ ; the substituent of the 5-6 membered heterocycloalkyl is selected from -OH, or C _1-6 alkyl; R ^a and R ^b are each independently selected From -H, or C _1-4 alkyl; -CH ₂ - on the C _3-12 cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S( =O) ₂ -substitution; the substituent of the C _3-12 cycloalkyl group is selected from -H, deuterium, C _1-6 hydroxyalkyl group, -C(O)NH ₂ , -OH, -COOH, halogen, substitution Or unsubstituted 5-6 membered heteroaryl, -CF ₃ , C _1-6 alkyl, -NH ₂ , C _1-6 alkoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or C _2-6 alkynyl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _{1- 6} haloalkyl, or C _1-6 alkyl; -CH ₂ - on the 4-10 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S (=O) ₂ -replacement; the 4-10-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the 4-10-membered heterocycloalkyl group is selected from C _{1- 6-} hydroxyalkyl, -CF ₃ , -OH, -COOH, C _1-6 alkyl, C _1-6 carbonyl, -S(O) ₂ CH ₃ , 4-6 membered heterocycloalkyl, 5-6 membered Heteroaryl, C _2-6 alkynyl, or halogen-substituted phenyl; the 4-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl The 5-8-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S; the 5-8-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S; the 5-8-membered heteroaryl group The substituent is selected from C _1-6 alkyl, halogen, -COOH, or -CF ₃ ; the substituent of the C _6-9 aryl group is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, - COOH, or -B(OH) ₂ ; further, R ₄ 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 alkynyl, , , ,or ; The substituent of the C _1-6 alkyl group is selected from -H, deuterium, halogen, -OH, -C(O)NH ₂ , substituted or unsubstituted 5-6 membered heteroaryl, C _3-6 cycloalkyl base, substituted or unsubstituted 5-6 membered heterocycloalkyl, C _1-4 alkoxy, or C _2-4 alkynyl; the 5-6 membered heteroaryl contains 1 to 3 selected from N, O Or a heteroatom of S; the 5-6-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; -CH ₂ - on the 5-6-membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -replacement; the substituent of the 5-6 membered heteroaryl is selected from halogen, C _1-4 alkyl, - NH ₂ , -OH, or -CF ₃ ; the substituent of the 5-6 membered heterocycloalkyl group is selected from -OH, or C _1-4 alkyl group; -CH ₂ on the C _3-10 cycloalkyl ring - optionally replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the substituent of the C _3-10 cycloalkyl group is selected from -H, deuterium, C _1-4 hydroxyalkyl, -C(O)NH ₂ , -OH, halogen, substituted or unsubstituted 5-6 membered heteroaryl, -CF ₃ , C _1-4 alkyl, -NH ₂ , C _{1 -4} alkoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or C _2-4 alkynyl; the 5-6 membered heteroaryl contains 1 to 4 selected from N, O or Heteroatom of S; the substituent of the 5-6 membered heteroaryl is selected from C _1-4 haloalkyl or C _1-4 alkyl; -CH ₂ - on the 4-10 membered heterocycloalkyl ring is any Selected to be replaced by -C(=O)-, -C(=S)-, or -S(=O) ₂ -; the 4-10-membered heterocycloalkyl group contains 1 to 3 selected from N, O or S heteroatoms; the substituents of the 4-10 membered heterocycloalkyl are selected from C _1-4 hydroxyalkyl, -CF ₃ , -OH, C _1-4 alkyl, C _1-4 carbonyl, -S(O ) ₂ CH ₃ , 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C _2-4 alkynyl, or halogen-substituted phenyl; the 4-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 5-6-membered heteroaryl group contains 1 to 3 heteroatoms selected from Heteroatom of N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _1-4 alkyl, halogen, or -CF ₃ ; the substituent of the C _6-9 aryl group is selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, or -B(OH) ₂ ; further, R ₄ is selected from C _1-8 alkyl, substituted C _1-6 alkyl, , , , , , , , , , , , substituted C _3-7 cycloalkyl, substituted 4-6 membered heterocycloalkyl, , , , , , , , , , , , , substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted phenyl, C _2-4 alkynyl, , , ,or ; The substituent of the C _1-6 alkyl group is selected from -H, deuterium, -F, -Cl, -Br, -OH, -C(O)NH ₂ , cyclopropyl, methoxy, ethynyl, , , , , , , , , , , , , , , ,or ; The substituent of the C _3-7 cycloalkyl group is selected from -H, deuterium, hydroxymethyl, , -C(O)NH ₂ , -OH, -F, -Cl, -Br, , , , , -CF ₃ , methyl, ethyl, -NH ₂ , methoxy, -NHC(O)CH ₃ , -NHS(O) ₂ CH ₃ , or ethynyl; the 4-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; the substituents of the 4-6 membered heterocycloalkyl are selected from C _1-4 hydroxyalkyl, -CF ₃ , -OH, C _1-4 alkyl , C _1-4 carbonyl group, -S(O) ₂ CH ₃ , , , pyridyl, pyrimidinyl, thienyl, pyridyl, pyridyl, C _2-4 alkynyl, or chlorine-substituted phenyl; the 5-6 membered heteroaryl is selected from pyridyl, thiazolyl, isotriyl Azolyl, pyrazolyl; the substituent of the 5-6 membered heteroaryl is selected from C _1-4 alkyl, halogen, or -CF ₃ ; the substituent of the phenyl is selected from halogen, C _1-4 alkyl , C _1-4 haloalkyl, or -B(OH) ₂ ; Furthermore, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Preferably, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Further preferably, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Further preferably, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Most preferably, R ₄ is selected from tertiary butyl, , , , , , , , , , , , , , , , ,or . The compound according to any one of claims 1-4, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula V: Formula V wherein, R ₁ , R ₂ and R ₃ are defined as shown in any one of claims 1 to 4. The compound according to claim 6, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula Va: Formula Va wherein, R ₂ and R ₃ are defined as shown in any one of claims 1-4. The compound according to claim 7, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula Vaa or Vab: Formula Vaa, Formula Vab wherein, R ₂ and R ₃ are defined as shown in any one of claims 1-4. The compound according to claim 1 or 5, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula VI: Formula VI Where, R ₄ is defined as shown in claim 1 or 5. The compound according to claim 1 or 5, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula VII: Formula VII Where, R ₄ is defined as shown in claim 1 or 5. The compound according to claim 1 or 5, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula VIII: Formula VIII Where, R ₄ is defined as shown in claim 1 or 5. A compound represented by formula (1), or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer: Formula (1) wherein, R ₁₁ 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 group, C _1-8 deuterated alkoxy group, halogen, or nitrile group; R ₁₂ is selected from -H, C _1-8 alkyl group, C _3-8 cycloalkyl group, C _1-8 haloalkyl group, C _{1- 8} deuterated alkyl, C _1-8 hydroxyalkyl, or C _2-8 alkynyl; R ₁₃ is selected from C _6-10 aryl that is unsubstituted or substituted by one or more identical or different substituents, A 5-10-membered heteroaryl group that is unsubstituted or substituted by one or more identical or different substituents; the 5-10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the The substituent of the C _6-10 aryl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the 5-10 membered heteroaryl group Selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; R ₁₄ is selected from C _2-8 alkynyl, unsubstituted or substituted by 1 or more C _6-10 aryl substituted by the same or different substituents, C _5-12 bridged cycloalkyl unsubstituted or substituted by 1 or more same or different substituents, unsubstituted or substituted by 1 or more 5-10 membered heteroaryl substituted with the same or different substituents, or ; The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the substituent of the C _6-10 aryl group is selected from halogen, -B(OH) ₂ , C _1-8 Alkyl, C _1-8 haloalkyl, or -COOH; the substituent of the 5-10 membered heteroaryl is selected from halogen, C _1-8 alkyl, -COOH, -C(O)NR ^e R ^f , or C _1-8 haloalkyl; the substituent of the C _5-12 bridged cycloalkyl is selected from -OH; R ₁₅ and R ₁₆ are each independently selected from -H, C _1-8 alkyl, C _1-8 haloalkyl , C _1-8 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a C _3-12 cycloalkyl group that is unsubstituted or substituted by one or more identical or different substituents, or 3-10 membered heterocycloalkyl that is unsubstituted or substituted by 1 or more identical or different substituents; the 3-10 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O or S ; The substituent of the C _3-12 cycloalkyl group is selected from deuterium, C _1-8 hydroxyalkyl group, C _1-8 haloalkyl group, C _1-8 alkyl group, -C(O)NR ^e R ^f , -NR ^e R ^f , -COOR ^e , halogen, -OH, C _1-8 alkoxy group; the substituent of the 3-10 membered heterocycloalkyl group is selected from C _1-8 hydroxyalkyl group, C _1-8 haloalkyl group, -OH, -COOR ^e , -C(O)NR ^e R ^f , C _1-8 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is 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, C _1-8 hydroxyalkyl, C _1-8 alkoxy C _1-8 alkyl, C _3-8 cycloalkyl, unsubstituted or 1 or more the same or different A 5-6 membered heteroaryl group substituted with a substituent, or a 4-6 membered heterocycloalkyl group that is unsubstituted or substituted by one or more identical or different substituents; the 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S; the 4-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S; the substituents of the 5-6 membered heteroaryl group Selected from C _1-8 alkyl, halogen, -NR ^e R ^f , -OH, C _1-8 haloalkyl, or C _1-8 deuterated alkyl; the substituent of the 4-6 membered heterocycloalkyl is selected from From C _1-8 alkyl, -OH, or -S(O) ₂ R ^g ; ^Re , R ^f , and R ^g are each independently selected from -H, or C _1-4 alkyl. The compound according to claim 12, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein R ₁₁ is selected from -H, C _1-6 alkane base, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, halogen, or nitrile group; Preferably, R ₁₁ 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, or Halogen; further, R ₁₁ is selected from C _1-4 alkyl, cyclopropyl, C _1-4 deuterated alkyl, C _1-4 alkoxy, C _1-4 deuterated alkoxy, or halogen; Further, R ₁₁ is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy , butoxy, pentyloxy, hexyloxy, -F, -Cl, -Br, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, deuterated pentyl, deuterated hexyl , deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated butoxy, deuterated pentyloxy, or deuterated hexyloxy; further, R ₁₁ is selected from methyl, methoxy group, -CD ₃ , -O-CD ₃ , -F, -Cl, -Br, or -CF ₃ ; further, R ₁₁ is selected from methyl, -CD ₃ , -F, -Cl, -Br, or -CF ₃ ; Most preferably, R ₁₁ is selected from methyl. The compound according to claim 12 or 13, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein R ₁₂ 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, or C _2-6 alkynyl; preferably, R ₁₂ is selected From -H, C _1-6 alkyl, C _3-4 cycloalkyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, ; Further, R ₁₂ 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 halo Hexyl; further, R ₁₂ is selected from -H, C _1-4 alkyl, C _1-4 deuterated alkyl, cyclopropyl, or C _1-4 haloalkyl; further, R ₁₂ is selected from -H, Methyl, ethyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, or -CD ₃ ; further, R ₁₂ is selected from -H, methyl, -CHF ₂ , -CF ₃ , or -CD ₃ ; Further, R ₁₂ is selected from methyl, or -CD ₃ ; Most preferably, R ₁₂ is selected from methyl. The compound according to any one of claims 12-14, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein: R ₁₃ is selected from unsubstituted or phenyl substituted by one or more identical or different substituents, unsubstituted or pyridyl substituted by one or more identical or different substituents, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 8} alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, or -CN; Preferably, R ₁₃ is selected from unsubstituted or substituted by 1, 2, 3 or 4 identical or different phenyl substituted by a base, pyridyl unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents, , ,or ; The substituent of the phenyl group is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN; the substituent of the pyridyl group is selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, or -CN; further, R ₁₃ is selected from unsubstituted or substituted by 1, 2 or 3 identical or different substituents Phenyl, pyridyl unsubstituted or substituted by 1, 2 or 3 identical or different substituents, or ; The substituent of the phenyl group is selected from -F, -Cl, -Br, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, or -CN; the substituent of the pyridyl group Selected from -F, -Cl, -Br, or C _1-4 alkyl; further, R ₁₃ is selected from , , , , , , , , , , , , , , , , , ,or ; Furthermore, R ₁₃ is selected from , , , , , , , , , , , , , , , ,or ; Further, R ₁₃ is selected from , , , , , , , , , , , , ,or ; Further, R ₁₃ is selected from , , , , ,or ; Most preferably, R ₁₃ is selected from , ,or . The compound according to any one of claims 12 to 15, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, wherein: R ₁₄ is selected from C _{2 -6} alkynyl, unsubstituted or phenyl substituted by one or more identical or different substituents, C _5-10 bridged cycloalkyl unsubstituted or substituted by one or more identical or different substituents , unsubstituted or pyridyl substituted by one or more identical or different substituents, or ; The substituent of the phenyl group is selected from halogen, -B(OH) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, or -COOH; the substituent of the pyridyl group is selected from halogen, C _1-6 Alkyl, -COOH, -C(O)NR ^e R ^f , or C _1-6 haloalkyl; the substituent of the C _5-10 bridged cycloalkyl is selected from -OH; R ₁₅ and R ₁₆ are each independently selected From -H, C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected are selected from the group consisting of unsubstituted or substituted by one or more A C _3-10 cycloalkyl group substituted with the same or different substituents, or a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted with 1 or more same or different substituents; the 3-8 membered heterocycloalkyl group The cycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; the substituents of the C _3-10 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, or C _1-6 alkoxy; the 3-8 membered heterocycloalkyl The substituent is selected from C _1-6 hydroxyalkyl, C _1-6 haloalkyl, -OH, -COOR ^e , -C(O)NR ^e R ^f , C _1-6 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is 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, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered heteroaryl unsubstituted or substituted by 1 or more identical or different substituents, or unsubstituted or substituted by 1 or more identical or different substituents 4-6 membered heterocycloalkyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O or S; the 4-6 membered heterocycloalkyl contains 1 to 2 selected from N , O or S heteroatom; the substituent of the 5-6 membered heteroaryl is selected from C _1-6 alkyl, halogen, -NR ^e R ^f , -OH, C _1-6 haloalkyl, or C _{1- 6} deuterated alkyl; the substituent of the 4-6 membered heterocycloalkyl is selected from C _1-6 alkyl, -OH, or -S(O) ₂ R ^g ; R ^e , R ^f , and R ^g are each independent is selected from -H, or C _1-4 alkyl; further, R ₁₄ is selected from C _2-6 alkynyl, unsubstituted or phenyl substituted by one or more identical or different substituents, unsubstituted Or C _5-10 bridged cycloalkyl substituted by 1 or more identical or different substituents, unsubstituted or pyridyl substituted by 1 or more identical or different substituents, or ; The substituent of the phenyl group is selected from halogen or -B(OH) ₂ ; the substituent of the pyridyl group is selected from halogen; the substituent of the C _5-10 bridged cycloalkyl group is selected from -OH; R ₁₅ , R ₁₆ is each independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a group selected from unsubstituted or C _3-10 cycloalkyl substituted by 1 or more identical or different substituents, or 3-8 membered heterocycloalkyl unsubstituted or substituted by 1 or more identical or different substituents; the The 3-8 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; the substituent of the C _3-10 cycloalkyl group is selected from halogen, -OH, or C _1-6 alkoxy group ; The substituent of the 3-8-membered heterocycloalkyl is selected from C _1-6 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is selected from -H, -CN, -C(O)NR ^e R ^f , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkynyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy C _1-6 Alkyl, C _3-6 cycloalkyl, 5-6 membered heteroaryl unsubstituted or substituted by 1 or more identical or different substituents, or unsubstituted or substituted by 1 or more identical or different substituents 4-6 membered heterocycloalkyl substituted by substituents; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O or S; the 4-6 membered heterocycloalkyl contains 1 to 2 A heteroatom selected from N, O or S; the substituent of the 5-6 membered heteroaryl is selected from C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 deuterated alkyl; the The substituents of the 4-6 membered heterocycloalkyl are selected from C _1-6 alkyl, or -OH; R ^e , R ^f , and R ^g are each independently selected from -H, or C _1-4 alkyl; further Ground, R ₁₄ is selected from C _2-4 alkynyl, unsubstituted or phenyl substituted by 1, 2 or 3 identical or different substituents, , , , unsubstituted or pyridyl substituted by 1, 2 or 3 identical or different substituents, or ; The substituent of the phenyl group is selected from halogen, or -B(OH) ₂ ; the substituent of the pyridyl group is selected from halogen; R ₁₅ and R ₁₆ are each independently selected from -H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form C selected from unsubstituted or substituted by 1, 2 or 3 identical or different substituents _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl that is unsubstituted or substituted by 1, 2 or 3 identical or different substituents; the 3-8 membered heterocycloalkyl contains 1 to 2 A heteroatom selected from N, O or S; the substituent of the C _3-8 cycloalkyl group is selected from halogen, -OH, C _1-4 alkoxy group; the substituent of the 3-8 membered heterocycloalkyl group Selected from C _1-4 alkyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is selected from -H, -CN, -C(O)NR ^e R ^f , C _{1- 4} alkyl, C _1-4 haloalkyl, C _2-4 alkynyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl, unsubstituted or 5-6 membered heteroaryl substituted by 1, 2 or 3 identical or different substituents, or 5-6 unsubstituted or substituted by 1, 2 or 3 identical or different substituents The 5-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N and O; the 5-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N and O ; The substituent of the 5-6 membered heteroaryl group is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuterated alkyl; the substituent of the 5-6 membered heterocycloalkyl group is selected from From C _1-4 alkyl, or -OH; ^Re , R ^f and R ^g are each independently selected from -H, or C _1-4 alkyl; Furthermore, R ₁₄ is selected from C _2-4 alkynyl , unsubstituted or phenyl substituted by 1 or 2 identical or different substituents, , , , unsubstituted or pyridyl substituted by 1 or 2 identical or different substituents, or ; The substituent of the phenyl group is selected from -F, -Cl, -Br, or -B(OH) ₂ ; the substituent of the pyridyl group is selected from -F, -Cl, or -Br; R ₁₅ and R ₁₆ are each Independently selected from -H, methyl, ethyl, isopropyl, tertiary butyl, -CF ₃ , -CH ₂ F, or hydroxymethyl; or R ₁₅ , R ₁₆ and the carbon atoms to which they are connected form a selected From cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _4-7 cycloalkyl substituted by 1 or 2 identical or different substituents, unsubstituted or substituted by 1 or 2 identical or different A 4-8-membered heterocycloalkyl group substituted with a substituent; the 4-8-membered heterocycloalkyl group contains 1 heteroatom selected from N, O or S; the substituent of the C _4-7 cycloalkyl group is selected from -F, -Cl, -Br, -OH, methoxy, or ethoxy; the substituent of the 4-8 membered heterocycloalkyl is selected from methyl, ethyl, -C(O)R ^e , or -S(O) ₂ R ^g ; R ₁₇ is selected from -H, -CN, -C(O)NR ^e R ^f , methyl, ethyl, -CF ₃ , ethynyl, C _1-4 hydroxyalkyl, Methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, unsubstituted or 5-membered heteroaryl substituted by 1 substituent, or unsubstituted or 1 or 2 identical or different A 5-6 membered heterocycloalkyl group substituted with a substituent; the 5-membered heteroaryl group contains 2 to 3 heteroatoms selected from N; the 5-6 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from O Heteroatom; the substituent of the 5-membered heteroaryl group is selected from methyl, ethyl, isopropyl, -CF ₃ , or -CD ₃ ; the substituent of the 5-6 membered heterocycloalkyl group is selected from methyl, Ethyl, or -OH; R ^e , R ^f , and R ^g are each independently selected from -H, methyl, or ethyl; further, R ₁₄ is selected from , tertiary butyl, isopropyl, , , , , , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Preferably, R ₁₄ is selected from , , , , , , , , , tertiary butyl, , , , , , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Preferably, R ₁₄ is selected from , , , , , , cyclobutyl, , , , , , , , , , , , , , , , , , , , , , , , ,or ; Preferably, R ₁₄ is selected from , , , , , , , , , , , ,or ; Preferably, R ₁₄ is selected from , , , ,or ; Most preferably, R ₁₄ is selected from . The compound according to any one of claims 12-15, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, having the structure represented by formula (2) : Formula (2) wherein R ₁₁ , R ₁₂ and R ₁₃ are defined as shown in any one of claims 12 to 15. The compound according to claim 17, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has a structure represented by formula (2-A): Formula (2-A) where R ₁₃ is defined as shown in claim 12 or 15. The compound according to claim 18, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, having formula (2-Aa) or formula (2-Ab ) shows the structure: Formula (2-Aa) Formula (2-Ab) wherein R ₁₃ is defined as in claim 12 or 15. The compound according to claim 12 or 16, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure shown in formula (3): Formula (3) where R ₁₄ is defined as shown in claim 12 or 16. The compound according to claim 12 or 16, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure shown in formula (4): Formula (4) where R ₁₄ is defined as shown in claim 12 or 16. The compound according to claim 12 or 16, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, has the structure shown in formula (5): Formula (5) where R ₁₄ is defined as shown in claim 12 or 16. The compound according to any one of claim 12, 15 or 16, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, having formula (6) Show structure: Formula (6) wherein R ₁₃ and R ₁₄ are defined as shown in any one of claims 12, 15 or 16. The compound according to any one of claims 1-23, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, which is selected from the following compounds At least one of: . A pharmaceutical composition comprising: The compound as described in any one of claims 1-24, its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer; and Pharmaceutically acceptable auxiliary ingredients. A compound as described in any one of claims 1-24, its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer or a drug as described in claim 25 Use of the composition in the preparation of a medicament against HBV infection.