BR112019024393B1 - HEPATITIS B VIRUS SURFACE ANTIGEN INHIBITOR COMPOUNDS, PHARMACEUTICAL COMPOSITION INCLUDING SAID COMPOUNDS AND USES THEREOF - Google Patents

Abstract

Disclosed herein is a novel 11-oxo-7,11-dihydro-6h-benzo-[f]pyrido[1,2-d][1,4]azepine oxepin-10-carboxylic acid derivative which serves as an inhibitor of hepatitis B virus surface antigen. Specifically disclosed is a compound represented by formula (V) or a pharmaceutically acceptable salt thereof and applications of the compound represented by formula (V) or the pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in the treatment of viral hepatitis B.

Description

Cross-reference to related orders

[001] This application claims priority to Chinese Patent Application No. CN201710365328.7 filed on May 22, 2017, the contents of which are incorporated herein by reference in their entirety.

Field of invention

[002] The present invention relates to a novel 11-oxo-7,11-dihydro-6H-benzo[f]pyrido[1,2-d][1,4]oxazepine-10-carboxylic acid derivative serving as an inhibitor of hepatitis B virus surface antigen. Specifically disclosed is a compound represented by formula (V) or a pharmaceutically acceptable salt thereof and the use of the compound represented by formula (V) or the pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in the treatment of viral hepatitis B.

State of the art

[003] Viral hepatitis B, abbreviated as hepatitis B, is a disease caused by Hepatitis B Virus (HBV) infection in the body. Hepatitis B virus is a hepadnaviridae that mainly exists in hepatocytes and causes damage to hepatocytes, resulting in inflammation, necrosis and fibrosis of hepatocytes. Viral hepatitis B is divided into acute hepatitis B and chronic hepatitis B. Most adults with acute hepatitis B can recover through their inherent immune function. However, chronic hepatitis B (CHB) has become a major healthcare challenge around the world; it is also the leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). An estimated 2 billion people worldwide are infected with chronic hepatitis B virus and more than 350 million people have progressed to hepatitis B. Every year, approximately 600,000 people die from complications of chronic hepatitis B. China is an area with a high prevalence of hepatitis B, and there are many patients with hepatitis B, which is a serious danger. According to the data, there are about 93 million people infected with hepatitis B virus in China, and about 20 million of them are diagnosed with chronic hepatitis B, 10% to 20% of whom may progress to cirrhosis and 1% to 5% of whom may progress to hepatocellular carcinoma.

[004] The key to functional cure of hepatitis B is to eliminate HBsAg (hepatitis B virus surface antigen) and produce surface antibodies. Quantification of HBsAg is a very important biological indicator. In chronically infected patients, a decrease in HBsAg and seroconversion, which is the end point of current treatment, are rarely observed.

[005] Hepatitis B virus (HBV) surface antigen protein plays a very important role in the process of HBV invasion into liver cells and is of great significance for preventing and treating HBV infection. Surface antigen proteins include large (L), medium (M) and small (S) surface antigen proteins that share a common C-terminal S region. They are expressed from an open reading frame, the different lengths of which are determined by the three AUG initiation codons of the reading frame. These three surface antigen proteins include pre-S1/pre-S2/S, pre-S2/S and S domains. HBV surface antigen protein is integrated into the endoplasmic reticulum (ER) membrane, which is initiated by the N-terminal signal sequence. Not only do these form the basic structure of virions, but they also form globular and filamentous subviral particles (SVPs, HBsAg) that accumulate in ER, host ER and pre-Golgi complex, and SVP contains most of the surface S antigen proteins. The L protein is critical in virus morphogenesis and nucleocapsid interaction, but is not required for SVP formation. Due to their lack of nucleocapsids, SVPs are not infectious. SVPs are highly involved in disease progression, especially in response to hepatitis B virus. In the blood of infected individuals, the content of SVPs is at least 10,000 times higher than the virus, arresting the immune system and weakening the body's immune response to hepatitis B virus. HBsAg also inhibits human innate immunity, inhibits the production of polysaccharide-induced cytokines (LPS) and IL-2, and inhibits DC function of dendritic cells and the induction activity of ERK-1/2 and c-Jun N-terminal kinase-1/2 in monocytes by LPS. It is noteworthy that disease progression in cirrhosis and hepatocellular carcinoma is also largely associated with persistent HBsAg secretion. These results suggest that HBsAg plays an important role in the progression of chronic hepatitis.

[006] Currently approved anti-HBV drugs are mainly immunomodulators (interferon-α and peginterferon-α-2α) and therapeutic antiviral drugs (Lamivudine, Adefovir Dipivoxil, Entecavir, Telbivudine, Tenofovir, Clevudine, etc.). Among these, antiviral drugs belong to nucleotides, and their mechanism of action is to inhibit HBV DNA synthesis rather than directly reduce HBsAg levels. As long-term treatment, the HBsAg clearance rate exhibited by nucleotide drugs is similar to natural observations.

[007] Clinically available therapies show little efficacy in reducing HBsAg. Therefore, the development of oral small molecule inhibitors that can effectively reduce HBsAg is currently needed for clinical use.

[008] Roche has developed a surface antigen inhibitor called RG7834 to treat hepatitis B and reported the efficacy of this compound in the woodchuck model against hepatitis B: RG7834, as a single drug, can reduce 2.57 Log of surface antigens and 1.7 Log of HBV-DNA. The compound shows good activity, but it is necessary to separate the isomers in the molecular synthesis process, which reduces the yield and increases the cost. The present invention obtains new compounds with higher anti-hepatitis B biological activity, a more compact synthetic process and better pharmaceutical properties by structural modification.

[009] WO2017013046A1 discloses a series of 2-oxo-7,8-dihydro-6H-pyrido[2,1,a][2]benzazepine-3-carboxylic acid derivatives (the general structure shown below) for treating or preventing hepatitis B virus infection. Embodiment 3 exhibiting the highest activity among this series of ring-fused compounds has an IC50 of 419 nM which can be further highly potentiated. The chiral centers contained in this series of compounds are difficult to synthesize asymmetrically. Typically, the 7-membered carbon ring has poor aqueous solubility and is susceptible to oxidative metabolism.

Contents of the present invention

[010] The present invention provides a compound of formula (V), an isomer thereof or a pharmaceutically acceptable salt thereof, wherein, the carbon atom marked with an "*" is a chiral carbon atom, which is in the form of a single enantiomer (R) or a single enantiomer (S) or enriched in one enantiomer; R1 is H, OH, CN, NH2, or selected from the group consisting of C1-6 alkyl, C1-6 heteroalkyl, C2-5 alkenyl, C2-5 heteroalkenyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R; R2 is H, OH, CN, NH2, halogen, or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R; R3 is selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R; m is 0, 1, 2, 3, 4 or 5; R1 is not OH, CN, NH2 as long as m is 0; Re is H, halogen, OH, CN, NH2 or selected from the group consisting of C1-3 alkyl and C1-3 heteroalkyl, each of which is optionally substituted with 1, 2 or 3 R';R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2 and CH2F; "hetero" refers to the heteroatom or heteroatomic group; the "hetero" in C1-6 heteroalkyl, C2-5 heteroalkenyl, 3- to 6-membered heterocycloalkyl, C1-3 heteroalkyl is independently selected from the group consisting of -C(=O)N(R)-, -N(R)-, -C(=NR)-, -(R)C=N-, -S(=O)2N(R)-, - S(=O)N(R)-, N, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- and - N(R)C(=O)N(R)-; in any of the above cases, the number of heteroatom or heteroatomic group is independently 1, 2, or 3.

[011] In some embodiments of the present invention, R is H, F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2, or CH2F.

[012] In some embodiments of the present invention R1 is H, OH, CN, NH2 or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C2-3 alkenyl, C2-3 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 R.

[013] In some embodiments of the present invention, R1 is H, OH, CN, NH or selected from the group consisting of each of which is optionally substituted with 1, 2 or 3 R.

[014] In some embodiments of the present invention, R1 is selected from the group consisting of H, OH, CN, NH2,

[015] In some embodiments of the present invention, R2 is H, OH, CN, NH2, halogen, or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R.

[016] In some embodiments of the present invention, R2 is H, OH, CN, NH2, F, Cl, Br, I or selected from the group consisting of CH3, each of which is optionally substituted with 1, 2 or 3 R.

[017] In some embodiments of the present invention, R2 is selected at ° A. from the group consisting of Cl, Br, CN, CH3,

[018] In some embodiments of the present invention, R3 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R.

[019] In some embodiments of the present invention, R3 is selected from the group consisting of

[020] In some embodiments of the present invention, m is selected from the group consisting of 0, 1, 2, 3, and 4; and R1 is not OH, CN, NH2 as long as m is 0.

[021] In some embodiments of the present invention, the fraction is selected from the group consisting of

[022] In some embodiments of the present invention, the compound, the isomer thereof or the pharmaceutically acceptable salt thereof, wherein the carbon atom marked with an "*" is a chiral carbon atom, which is in the form of a single enantiomer (R) or enriched in an enantiomer.

[023] In some embodiments of the present invention, R is H, F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2 or CH2F and other variables are as defined above.

[024] In some embodiments of the present invention R1 is H, OH, CN, NH2 or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C2-3 alkenyl, C2-3 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined above.

[025] In some embodiments of the present invention, R1 is H, OH, CN, NH or selected from the group consisting of CH3, each of which is optionally replaced with 1, 2, or 3 R and other variables are as defined above.

[026] In some embodiments of the present invention, R1 is selected from the group consisting of H, OH, CN, NH2, and other variables are as defined above.

[027] In some embodiments of the present invention, R2 is H, OH, CN, NH2, halogen or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined above.

[028] In some embodiments of the present invention, R2 is H, OH, CN, NH2, F, Cl, Br, I, or selected from the group consisting of CH3, , each of which is optionally replaced with 1, 2, or 3 R and other variables are as defined above.

[029] In some embodiments of the present invention, R2 is selected from the group consisting of Cl, Br, CN, CH3, and other variables are as defined above.

[030] In some embodiments of the present invention, R3 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined above.

[031] In some embodiments of the present invention, R3 is selected from the group consisting of and other variables are as defined above.

[032] In some embodiments of the present invention, m is selected from the group consisting of 0, 1, 2, 3, and 4; and R1 is not OH, CN, NH2 provided that m is 0, and other variables are as defined above.

[033] In some embodiments of the present invention, the fraction is selected from the group consisting of and and other variables are as defined above.

[034] In some embodiments of the present invention, the compound, the isomer thereof or the pharmaceutically acceptable salt thereof, wherein the carbon atom marked with an "*" is a chiral carbon atom, which is in the form of a single enantiomer (R) or enriched in an enantiomer, and other variables are as defined above.

[035] In some embodiments of the present invention, the compound, isomer thereof or pharmaceutically acceptable salt thereof is selected from the group consisting of wherein, the carbon atom marked with a "*" is a chiral carbon atom, which is in the form of a single enantiomer (R) or one enantiomer (S) or enriched in one enantiomer; R4 is H or selected from the group consisting of C1-3 alkyl and C1-3 heteroalkyl, each of which is optionally substituted with 1, 2, or 3 R; X is selected from the group consisting of C and N; Y is selected from the group consisting of O and C; each of L1 and L2 is independently selected from the group consisting of a single bond, -(CH2)n-, and -C(=O)-; provided that L1 and L2 are not both a single bond; n is 1 or 2, m, R, R2, R3, and the "hetero" in C1-3 heteroalkyl are as defined above; and R4 is not H provided that m is 0.

[036] In some embodiments of the present invention, the compound, the isomer thereof or the pharmaceutically acceptable salt thereof, wherein the carbon atom marked with an "*" is a chiral carbon atom, which is in the form of a single enantiomer (R) or enriched in an enantiomer.

[037] The present invention also provides a compound, an isomer thereof or a pharmaceutically acceptable salt thereof wherein the compound is selected from the group consisting of

[038] In some embodiments of the present invention, the compound is selected from the group consisting of

[039] The present invention provides a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein, R1 is H, OH, CN, NH2 or selected from the group consisting of C1-6 alkyl, C1-6 heteroalkyl, C2-5 alkenyl, C2-5 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 R; R2 is H, OH, CN, NH2, halogen or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 R; R3 is selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R; m is 0, 1, 2, 3, 4, or 5; R1 is not OH, CN, NH2 as long as m is 0; Re is H, halogen, OH, CN, NH2, or selected from the group consisting of C1-3 alkyl and C1-3 heteroalkyl, each of which is optionally substituted with 1, 2, or 3 R';R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2, and CH2F; "hetero" refers to the heteroatom or heteroatomic group; the "hetero" in C1-6 heteroalkyl, C2-5 heteroalkenyl, 3- to 6-membered heterocycloalkyl, C1-3 heteroalkyl is independently selected from the group consisting of -C(=O)N(R)-, -N(R)-, -C(=NR)-, -(R)C=N-, -S(=O)2N(R)-, - S(=O)N(R)-, N, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- and - N(R)C(=O)N(R)-; in any of the above cases, the number of heteroatom or heteroatomic group is independently 1, 2, or 3.

[040] In some embodiments of the present invention, R is H, F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2, or CH2F.

[041] In some embodiments of the invention R1 is H, OH, CN, NH2 or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C2-3 alkenyl, C2-3 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 R.

[042] In some embodiments of the present invention, R1 is H, OH, CN, NH or selected from the group consisting of CH3, each of which is optionally substituted with 1, 2 or 3 R.

[043] In some embodiments of the present invention, R1 is H, OH, CN, NH2,

[044] In some embodiments of the present invention, R2 is H, OH, CN, NH2, halogen, or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R.

[045] In some embodiments of the present invention, R2 is H, OH, CN, NH2, F, Cl, Br, I, or selected from the group consisting of CH3, each of which is optionally substituted with 1, 2 or 3 R.

[046] In some embodiments of the present invention, R2 is selected from the group consisting of Cl, Br, CN, CH3,

[047] In some embodiments of the present invention, R3 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R.

[048] In some embodiments of the present invention, R3 is selected from the group consisting of

[049] In some embodiments of the present invention, m is selected from the group consisting of 0, 1, 2, 3, and 4; and R1 is not OH, CN, NH2 as long as m is 0.

[050] In some embodiments of the present invention, the fraction is selected from the group consisting of

[051] In some embodiments of the present invention, the compound, isomer thereof or pharmaceutically acceptable salt thereof is selected from the group consisting of wherein, R4 is H or selected from the group consisting of C1-3 alkyl and C1-3 heteroalkyl, each of which is optionally substituted with 1, 2, or 3 R; X is selected from the group consisting of C and N; Y is selected from the group consisting of O and C; each of L1 and L2 is independently selected from the group consisting of a single bond, -(CH2)n-, and -C(=O)-; provided that L1 and L2 are not both a single bond; n is 1 or 2, m, R, R2, R3, and the "hetero" in C1-3 heteroalkyl are as defined above; and R4 is not H provided that m is 0.

[052] The present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

[053] In some embodiments of the present invention, the compound is selected from the group consisting of

[054] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[055] The present invention also provides a use of the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition in the manufacture of a medicament for treating hepatitis B.

[056] In some embodiments of the present invention, R is H, F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2 or CH2F and other variables are as defined above.

[057] In some embodiments of the present invention R1 is H, OH, CN, NH2 or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C2-3 alkenyl, C2-3 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined above.

[058] In some embodiments of the present invention, R1 is H, OH, CN, NH or selected from the group consisting of CH3, each of which is optionally replaced with 1, 2, or 3 R and other variables are as defined above.

[059] In some embodiments of the present invention, R1 is selected from the group consisting of H, OH, CN, NH2, and other variables are as defined above.

[060] In some embodiments of the present invention, R2 is H, OH, CN, NH2, halogen or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined above.

[061] In some embodiments of the present invention, R2 is H, OH, CN, NH2, F, Cl, Br, I, or selected from the group consisting of CH3, , each of which is optionally replaced with 1, 2, or 3 R and other variables are as defined above.

[062] In some embodiments of the present invention, R2 is selected from the group consisting of Cl, Br, CN, CH3, and other variables are as defined above.

[063] In some embodiments of the present invention, R3 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 R and other variables are as defined above.

[064] In some embodiments of the present invention, R3 is selected from the group consisting of and other variables are as defined above.

[065] In some embodiments of the present invention, m is selected from the group consisting of 0, 1, 2, 3, and 4; and R1 is not OH, CN, NH2 provided that m is 0, and other variables are as defined above.

[066] In some embodiments of the present invention, the fraction is selected from the group consisting of and other variables are as defined above.

[067] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, the isomer or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[068] The present invention also provides a use of the compound, the isomer thereof or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament for treating hepatitis B.

[069] Other embodiments of the present invention may be obtained by arbitrary combination of the above variables.

Technical effect

[070] The present invention creatively designs and synthesizes a novel series of compounds with a seven-membered oxazepine as a core structure. The compounds of the present invention have high in vitro anti-HBV activity, and the EC50 values of the most active compounds in inhibiting HBV-DNA and HBsAg are below 1 nM. The chiral center of the compound of the present invention is prepared using commercial amino acids as raw materials, and the synthesis process is simple and economical. Compared with the prior art, after the carbon in the seven-membered ring is replaced by oxygen, the aqueous solubility of the compound is increased and the risk of oxidative metabolism is reduced, thereby obtaining better druggability.

[071] The compounds of the present invention have a moderate plasma protein binding rate and do not inhibit the cytochrome P450 isoenzyme, demonstrating a low risk of drug-drug interaction. The compounds of the present invention show excellent stability in the liver microsomes of three species of rats, humans and mice, indicating that the compounds are not easily metabolized. The compounds of the present invention show better exposure and bioavailability in the pharmacokinetic study in mice and rats. The compounds of the present invention exhibit good anti-HBV activity both in an in vivo pharmacodynamic study in a mouse model of HBV by hydrodynamic injection (HDI-HBV) through the tail vein and in a mouse model of hepatitis B virus (AAV-HBV) mediated by recombinant adeno-associated virus type 8 vector. The compounds of the present invention show good tolerance in the 14-day pre-toxicology test in rats and exhibit good tolerance in a single-dose neurotoxicity test.

[072] The compound of (R) configuration of the present invention has a 3- to 5-fold increase in anti-HBV activity compared to the racemic compound of the present invention and has a 10-fold increase in anti-HBV activity compared to the compound of (S) configuration of the present invention.

Definition and description

[073] Unless otherwise indicated, the following terms, when used in the descriptions and claims of the invention, have the following meanings. A specific term or phrase should not be considered undefined or uncertain in the absence of a specific definition, but should be understood in its ordinary sense. When a trade name is used in the present invention, it is intended to refer to its relative commodity or active ingredient thereof. The term "pharmaceutically acceptable" is used in the present invention in terms of those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, proportionate to a reasonable benefit/risk ratio.

[074] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the invention prepared by reacting the compound with a specific substitute of the invention with a relatively non-toxic acid or base. When the compound of the invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. The pharmaceutically acceptable base addition salt includes a sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts. When the compound of the invention contains a relatively basic functional group, a base addition acid can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salt include an inorganic acid salt, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and an organic acid salt, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and the like; and a salt of an amino acid (such as arginine and the like) and a salt of an organic acid, such as glucuronic acid and the like (referred to in Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention containing basic and acidic functional groups can be converted to any base or acid addition salt.

[075] Preferably, by contacting the salt with a base or an acid in the conventional manner, then separating the parent compound, the neutral form of the compound is thereby regenerated. The difference between the parent form of the compound and its various salt forms lies in specific physical properties, such as different solubility in a polar solvent.

[076] "Pharmaceutically acceptable salt" used in the present invention pertains to a derivative of the compound of the present invention, wherein the parent compound is modified by forming a salt with an acid or a base. Examples of the pharmaceutically acceptable salt include, but are not limited to, an inorganic acid or organic acid salt of a basic moiety such as an amine, an alkali metal salt or an organic salt of an acidic moiety such as a carboxylic acid, and the like. The conventionally acceptable salt includes a non-toxic conventional salt or quaternary ammonium salt of the parent compound, such as a salt formed by a non-toxic inorganic acid or an organic acid. Conventional non-toxic salt includes, but is not limited to, salt derived from an inorganic acid and an organic acid, wherein the inorganic acid or organic acid is selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalactanal acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid

[077] The pharmaceutically acceptable salt of the invention may be prepared from the parent compound containing an acidic or basic moiety by conventional chemical methods. In general, such a salt may be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred.

[078] Certain compounds of the invention may exist in an unsolvated form or a solvated form, including hydrated form. In general, the solvated form is equivalent to the unsolvated form and both are encompassed within the scope of the invention.

[079] Certain compounds of the present invention may have an asymmetric carbon atom (optical center) or a double bond. The racemate, diastereoisomer, geometric isomer, and individual isomer are all encompassed within the scope of the present invention.

[080] Unless otherwise indicated, the absolute configuration of a stereogenic center is represented by an embedded solid bond and an embedded dashed link , a wavy line represents a solid bond embedded p or an embedded dashed link , and the relative configuration of a stereogenic center is represented by a solid direct bond and a direct dashed connection . When the compound described in the present invention contains an olefinic double bond or other geometrically asymmetric centers, the E and Z geometric isomers are included, unless otherwise indicated. Similarly, all tautomeric forms are encompassed within the scope of the invention.

[081] Unless otherwise indicated, the terms "enriched in an isomer", "enriched in isomer", "enriched in an enantiomer" or "enantiomer-enriched" refer to the content of one of the isomers or enantiomers being less than 100% and the content of the isomer or enantiomer is 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, 99.9% or more.

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

[083] The compound of the invention may have a specific geometric or stereoisometric form. The invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R) and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, for example, an enriched mixture of enantiomers or diastereomers, all of which are encompassed within the scope of the invention. The substituent, such as alkyl, may have an additional asymmetric carbon atom. All such isomers and mixtures thereof are encompassed within the scope of the invention.

[084] Optically active (R) and (S) isomer or D and L isomer can be prepared using chiral synthesis or chiral reagents or other conventional techniques. If one type of enantiomer of a given compound of the invention is obtained, the desired pure enantiomer can be obtained by asymmetric synthesis or derivative action of chiral auxiliary followed by separation of the resulting diastereomeric mixture and cleavage of the auxiliary group. Alternatively, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), the compound is reacted with an appropriate optically active base or acid to form a salt of the diastereomeric isomer which is then subjected to diastereomeric resolution by the conventional method in the art to provide the pure enantiomer. In addition, the enantiomer and diastereoisomer are generally isolated by chromatography using a stationary phase and optionally combined with a chemical derivative method (such as carbamate generated from amine).

[085] The compound of the invention may contain an unnatural proportion of atomic isotope in one or more of the atom(s) constituting the compound. For example, the compound may be radiolabeled with a 3 125 14 raoactive isotope, such as tri( ), o-( ) or -( ). The isotopic variations of the compound of the invention, whether radioactive or not, are encompassed within the scope of the invention.

[086] The term "pharmaceutically acceptable carrier" refers to any agent or carrier medium capable of delivering an effective amount of the active substance of the present invention, which does not interfere with the biological activity of the active substance and does not have any toxic side effects on the host or patient. Representative carriers include water, oil, vegetable and mineral, cream base, lotion base, ointment base and the like. The base includes a suspending agent, a thickener, a penetration enhancer and the like. Their formulations are widely known to those skilled in the cosmetic or topical pharmaceutical field. Additional information on the carrier can be referenced in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[087] The term "excipient" generally refers to a carrier, diluent and/or vehicle necessary to formulate an effective pharmaceutical composition.

[088] For a drug or a pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount, but sufficient to achieve a desired effect of the drug or agent. For the oral dosage form of the present invention, an "effective amount" of the active substance in the composition refers to an amount necessary to achieve a desired effect when combining it with another active substance in the composition. The effective amount varies from person to person and is determined depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in an individual case can be determined by those skilled in the art on the basis of routine experience.

[089] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that can effectively treat the target disorder, disease or condition.

[090] "Optional" or "optionally" means that the subsequent event or condition may occur but is not required to occur; the term includes both the instance in which the event or condition occurs and the instance in which the event or condition does not occur.

[091] The term "substituted" means that one or more hydrogen atom(s) on a given atom are replaced by the substituent, including deuterium and hydrogen variants, provided that the valence of the given atom is normal and the substituted compound is stable. When the substituent is a ketone (i.e., =O), this means that two hydrogen atoms are replaced. Positions on an aromatic ring cannot be replaced by a ketone. The term "optionally substituted" means that an atom may or may not be replaced with a substituent, unless otherwise indicated; the type and number of substituents may be arbitrary, provided that it is chemically possible.

[092] When any variable (such as R) occurs in the constitution or structure of the compound more than once, the definition of the variable in each occurrence is independent. Thus, for example, if a group is substituted with 0 to 2 R, the group may be optionally substituted with up to two R, where the definition of R in each occurrence is independent. Furthermore, a combination of the substituent and/or the variant thereof is permitted only when the combination results in a stable compound.

[093] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single link.

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

[095] When a substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in AX, the structure of AX is actually A. When a bond of a substituent can be cross-linked to more than one atom in a ring, that substituent can be bonded to any atom in the ring. For example, the structural unit means that the substituent R may be located at any position in cyclohexyl or cyclohexadiene. When the enumerable substituent does not indicate by which atom it is bonded to the group to be substituted, such substituent may be bonded by any atom thereof. For example, when pyridyl acts as a substituent, it may be bonded to the group to be substituted with any carbon atom in the pyridine ring. When the enumerable linking group does not indicate the direction for bonding, the direction for bonding is arbitrary, for example, the linking group L contained in is -MW-, then -MW- can connect ring A and ring B to form in the same sense of the reading order from left to right and form in the opposite direction in the reading order from left to right. A combination of the substituent and/or variants thereof is permitted only when such a combination can result in a stable compound.

[096] Unless otherwise indicated, the term "hetero" represents a heteroatom or a heteroatomic group (e.g., an atomic group containing a heteroatom) including the atom other than carbon (C) and hydrogen (H) and the atomic group containing the above heteroatom, for example, including oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2- and the group consisting of -C(=O)N(H)-, -N(H)-, -C(=NH)-, - S(=O)2N(H)- and -S(=O)N(H)-, each of which is optionally substituted.

[097] Unless otherwise indicated, the term "ring" refers to a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The so-called ring includes a single ring, a double ring, a spiral ring, a fused ring or a bridged ring. The number of the atom in the ring is usually defined as the number of ring members, for example, a "5- to 7-membered ring" means that 5 to 7 atoms are arranged in a ring. Unless otherwise indicated, the ring optionally contains 1 to 3 heteroatoms. Therefore, a "5- to 7-membered ring" includes, for example, phenyl, pyridinyl and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but excluding phenyl. The term "ring" also includes a ring system containing at least one ring, each ring independently meeting the above definition.

[098] Unless otherwise indicated, the term "heterocycle" or "heterocyclic" refers to a stable monocyclic, bicyclic or tricyclic ring containing a heteroatom or heteroatom group, which may be saturated, partially unsaturated or unsaturated (aromatic) and may contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents already defined herein). The heterocycle may be attached to the pendant group of any heteroatom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycle described in the present invention may have a substitution at a carbon or nitrogen position. The nitrogen atom in the heterocycle is optionally quaternized. In a preferred embodiment, when the total number of S and O atoms of the heterocycle is greater than 1, the heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms of the heterocycle is not greater than 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" refers to a 7-, 8-, 9- or 10-membered bicyclic, 5-, 6- or 7-membered monocyclic or bicyclic heterocyclic aromatic ring, which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It is important to note that the total number of S and O atoms in an aromatic heterocycle is not greater than one. A bridging ring is also included in the definition of a heterocycle. A bridging ring is formed when one or more atoms (i.e., C, O, N, or S) bridge two nonadjacent carbon or nitrogen atoms. A preferred bridging ring includes, but is not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is important to note that a bridge always converts a monocyclic ring to a tricyclic ring. In a bridged ring, the substituent on the ring may also be present in the bridge.

[099] Examples of the heterocyclic compound include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazolyl, H-carbazolyl, carbolinyl , chromanyl, chromene, cinolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoindolyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxyindolyl, pyrimidinyl, phenantridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoloxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pirazinala, pirazolidinila, pirazolinila, pirazolila, piridazinila, pirido-oxazolila, pirido-imidazolila, pirido-tiazolila, piridinila, pirrolidinila, pirrolinila, 2H-pirrolila, pirrolila, quinazolinila, quinolinila, 4H-quinolizinila, quinoxalinila, quinuclidinila, tetra-hidrofuranila, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thiantrenyl, thiazolyl, isothiazolylthienyl, thieno-oxazolyl, thieno-thiazolyl, thieno-imidazolyl, thienyl, triazinyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl and xanthenyl. Also included are compounds of cast ring and spiro compounds.

[0100] Unless otherwise indicated, the term "hydrocarbyl" or its hyponyms (e.g., alkyl, alkenyl, alkynyl, and aryl, etc.), alone or as part of another substituent, refers to a branched, straight, cyclic chain hydrocarbon radical, or any combination thereof. These may be saturated (e.g., alkyl), mono- or polyunsaturated (e.g., alkenyl, alkynyl, and aryl), may be mono-, di- or polysubstituted, may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methenyl), may also include a divalent or multivalent group, have a specific number of carbon atoms (e.g., C1-C12 indicates 1 to 12 carbon atoms, C1-12 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12; C3-12 is selected from C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12). The term "hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl and aromatic hydrocarbyl. Aliphatic hydrocarbyl includes linear and cyclic hydrocarbyl, specifically including, but not limited to, alkyl, alkenyl, and alkynyl. Aromatic hydrocarbyl includes, but is not limited to, 6- to 12-membered aromatic hydrocarbyl, such as phenyl, naphthyl, and the like. In some embodiments, the term "hydrocarbyl" refers to a linear or branched group or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include a divalent or multivalent group. Examples of the saturated hydrocarbyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl and the homologue or isomer of n-amyl, n-hexyl, n-heptyl, n-octyl and other atomic groups. Unsaturated hydrocarbyl has one or more double or triple bonds. Examples of unsaturated alkyl include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and more higher homologues and isomers.

[0101] Unless otherwise indicated, the term "heterohydrocarbyl" or its hyponyms (such as heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, etc.), alone or as part of another substituent, refers to a linear, branched, or cyclic hydrocarbon group, or any combination thereof, having a specified number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" alone or in combination with another term refers to a stable straight chain, branched hydrocarbon radical or a combination thereof having a specified number of carbon atoms and at least one heteroatom. In a specific embodiment, a heteroatom is selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroatom group or heteroatom may be located at any position within a heterohydrocarbyl, including the position at which the hydrocarbyl attaches to the remainder of the molecule. However, the terms "alkoxy", "alkylamino", and "alkylthio" (or thioalkyl) are used as conventionally used and refer to an alkyl group attached to the remainder of the molecule through an oxygen atom, an amino atom, or a sulfur atom, respectively. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two consecutive heteroatoms may be present, such as, - CH2-NH-OCH3.

[0102] Unless otherwise indicated, the term "cyclohydrocarbyl", "heterocyclohydrocarbyl" or its hyponyms (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by itself or in conjunction with another term refers to "hydrocarbyl" or cyclized "heterohydrocarbyl". In addition, for heterohydrocarbyl or heterocyclocarbyl (e.g., heteroalkyl and heterocycloalkyl), a heteroatom may occupy the position where the heterocycle attaches to the remaining position of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, cyclopentyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro-thiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.

[0103] Unless otherwise indicated, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, may be mono-substituted (e.g., -CH2F) or poly-substituted (e.g., -CF3), may be monovalent (e.g., methyl), divalent (e.g., methylene) or multivalent (e.g., methenyl). Examples of alkyl include methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0104] Unless otherwise indicated, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds at any position in the chain, may be mono- or polysubstituted, and may be monovalent, divalent, or multivalent. Examples of alkenyl include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

[0105] Unless otherwise indicated, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any position in the chain, may be mono- or polysubstituted, and may be monovalent, divalent, or multivalent. Examples of alkynyl include ethylnyl, propynyl, butynyl, pentynyl, and the like.

[0106] Unless otherwise indicated, cycloalkyl includes any stable cyclic or polycyclic hydrocarbyl and any carbon atom that is saturated may be mono- or polysubstituted and may be monovalent, divalent or multivalent. Examples of cycloalkyl include, but are not limited to, cycloalkyl, norbornanyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecanyl and the like.

[0107] Unless otherwise indicated, cycloalkenyl includes any stable cyclic or polycyclic hydrocarbyl having one or more unsaturated carbon-carbon single bonds at any position in the ring, may be mono- or polysubstituted, and may be monovalent, divalent, or multivalent. Examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

[0108] Unless otherwise indicated, cycloalkynyl includes any stable cyclic or polycyclic hydrocarbyl having one or more carbon-carbon triple bonds at any position in the ring, may be mono- or poly-substituted, and may be monovalent, divalent, or multivalent.

[0109] Unless otherwise indicated, the term "halo" or "halogen" individually or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "haloalkyl (C1-C4)" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl.

[0110] The term "alkoxy" represents any alkyl defined above having a specified number of carbon atoms linked by an oxygen bridge. Unless otherwise indicated, C1-6 alkoxy includes C1, C2, C3, C4, C5 and C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentoxy.

[0111] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated aromatic substituent, which may be mono-, di- or polysubstituted, which may be monovalent, divalent or multivalent, which may be a single ring or a multiple ring (e.g., one to three rings; wherein each ring is aromatic), which are fused together or covalently connected. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatom is selected from B, O, N and S, wherein nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heteroaryl may be attached to the remainder of a molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolyl, -naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolium, 5-indolyl, lily, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. The substituent of any of the above aryl and heteroaryl ring systems is selected from the acceptable substituent described below.

[0112] Unless otherwise indicated, when aryl is combined with other terms (such as aryloxy, arylthio, aralkyl), aryl includes the heteroaryl and aryl ring as defined above. Thus, the term "aralkyl" is intended to include the group (e.g., benzyl, phenethyl, pyridylmethyl, etc.) in which an aryl is attached to an alkyl, including an alkyl in which the carbon atom (e.g., methylene) has been replaced by an atom such as oxygen, e.g., phenoxytyl, 2-pyridyloxy, 3-(1-naphthyloxy)propyl, and the like.

[0113] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonates, and the like; acyloxy, such as acetoxy, trifluoroketoxy, and the like.

[0114] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amine protecting group" refers to a protecting group suitable for blocking the side reaction at the nitrogen of an amino. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for blocking the side reaction at hydroxy. Representative hydroxy protecting groups include, but are not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0115] The compound of the present invention can be prepared by a variety of synthetic methods widely known to those skilled in the art, including the following enumerative embodiment, the embodiment formed by the following enumerative embodiment in conjunction with other chemical synthesis methods, and equivalent substitution widely known to those skilled in the art. The preferred embodiment includes, but is not limited to, the embodiment of the present invention.

[0116] The solvent used in the present invention is commercially available.

[0117] Compounds are named manually or by ChemDraw® software, commercially available compounds use their supplier directory names.

Brief description of the figures

[0118] Figure 1 illustrates the changes in the HBsAg content of mouse plasma after administration on different days.

[0119] Figure 2 illustrates the changes in the HBsAg content of mice after administration on different dates.

[0120] Figure 3 illustrates the changes in body weight of mice after daily dosing.

Detailed description of preferred modalities

[0121] The following examples further illustrate the present invention, but the present invention is not limited thereto. The present invention has been described in detail in the text and its specific embodiments have also been disclosed; to one skilled in the art, it will be obvious to modify and improve the embodiments of the present invention within the spirit and scope of the present invention. Embodiment 1

[0122] Step A: 1-1 (200.00 g, 1.19 mol) was dissolved in N,N-dimethylformamide (1000.00 mL), followed by addition of potassium carbonate (164.39 g, 1.19 mol). 1-Bromo-3-methoxy-propane (182.01 g, 1.19 mol) was added dropwise at 90 °C within one hour. The mixture was stirred at 90 °C for 15 hours. 3 L of ethyl acetate (1 L x 3) was added to the reaction mixture. The organic phases were combined, washed with 15.00 L of water (3.00 L x 5) and 3.00 L of saturated brine (1.00 L x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/0) to afford compound 12.

[0123] Step B: 1-2 (80.00 g, 332.98 mmol) was dissolved in acetonitrile (800.00 mL), followed by addition of chlorosuccinimide (44.46 g, 332.98 mmol), and the mixture was stirred at 90 °C for three hours. Half the volume of acetonitrile was first rotary evaporated, followed by addition of 200.00 mL of water and 300.00 mL of ethyl acetate. The isolated organic phase was washed with ammonium chloride solution (100.00 mL), dried over anhydrous sodium, and concentrated under reduced pressure to afford a yellow oily compound. The compound was triturated with methanol to afford 1-3.

[0124] Step C: Potassium carbonate (76.48 g, 553.34 mmol) was added to a solution of 1-3 (76.00 g, 276.67 mmol), benzyl bromide (52.05 g, 304.34 mmol, 36.15 mL) in N,N-dimethylformamide (800.00 mL). The mixed solution was stirred at 25 °C for 16 h. Ethyl acetate (900.00 mL) and water (1000.00 mL) were added to the solution. The organic phase was isolated and washed with water (1000.00 mL x 2) and saturated brine (300.00 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to furnish Compound 1-4.

[0125] Step D: 1-4 (92.00 g, 252.18 mmol) was dissolved in methanol (500.00 mL), followed by addition of potassium hydroxide solution (6 M, 239.99 mL). The mixture was stirred at 45 °C for 2 h. The pH of the reaction mixture was adjusted to with 3 to 6 M hydrochloric acid and a white solid was precipitated, followed by filtration to afford the solid. The solid was dissolved in dichloromethane (80 mmol), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 1-5.

[0126] Step E: 1-5 (76.58 g, 218.31 mmol) was dissolved in dichloromethane (500.00 mL), followed by addition of oxalyl chloride (41.56 g, 327.46 mmol, 28.66 mL) and N,N-dimethylformamide (159.56 mg, 2.18 mmol, 167.96 μL). The mixture was stirred at 25 °C for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure to furnish Compound 1-6.

[0127] Step F: 1-6 (63.00 g, 170.62 mmol) and methyl ethyl-2-(dimethylaminomethylidene)-3-oxo-butanoate (44.24 g, 238.87 mmol) were dissolved in tetrahydrofuran (600.00 mL) which were then added dropwise to a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.00 mol, 409.49 mL) at -70°C to -60°C. After the dropwise addition was complete, the dry ice acetone bath was removed and hydrochloric acid solution (3.00 mol, 832.06 mL) was added in one portion. The reaction mixture was stirred at 20°C for one hour. The mixture was filtered to provide a solid. The solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a solid. Methyl tert-butyl ether (60.00 mL) was added to the solid, stirred for 30 min, and filtered to give Compound 1-7.

[0128] 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.73-7.79 (m, 1H), 7.34-7.43 (m, 4H), 7.20 (s, 1H), 6.63 (s, 1H), 5.24 (s, 2H), 4.39 (q, J=7.15 Hz, 2H), 4.11 (t, J=6, 21 Hz, 2H), 3.59 (t, J=5.90 Hz, 2H), 3.38 (s, 3H), 2.05-2.12 (m, 2H), 1.40 (t, J= 7.15Hz, 3H).

[0129] Step G: 1-7 (2.00 g, 4.23 mmol) was dissolved in ethanol (30.00 mL), followed by addition of acetic acid (10.00 mL) and (R)-(-)-2-amino-1-butanol (565.59 mg, 6.35 mmol, 595.36 μL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and extracted with water (50.00 mL) and 60.00 mL of ethyl acetate (20.00 mLx3). The combined organic phase was washed with 20.00 mL (10.00 mLx2) of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude product. The crude product was purified by column chromatography (silica, eluent: petroleum ether/ethyl acetate = 10/1 to 1/1) to afford Compound 1-8.

[0130] Step H: 1-8 (1.80 g, 3.31 mmol) was dissolved in dichloromethane (20.00 mL), followed by addition of triethylamine (502.41 mg, 4.97 mmol, 688.23 μL) and addition of methanesulfonyl chloride (454.99 mg, 3.97 mmol, 307.43 μL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of 30.00 mL of water at 25 °C and then extracted with 100.00 mL of dichloromethane (50 mL × 2). The combined organic phase was washed with 60.00 mL (30.00 mLx2) of saturated brine, dried over anhydrous sulfate, filtered, and concentrated under reduced pressure to furnish Compound 1-9.

[0131] Step I: 1-9 (2.00 g, 3.21 mmol) was dissolved in tetrahydrofuran (100.00 mL), followed by addition of palladium carbon (300.00 mg, 10% purity) under a nitrogen atmosphere. The suspension was purified with hydrogen three times. The reaction mixture was stirred at 25 °C for 2 h under a hydrogen atmosphere (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to afford Compound 1-10.

[0132] Step J: 1-10 (1.70 g, 3.20 mmol) was dissolved in N,N-dimethylformamide (20.00 mL), followed by addition of potassium carbonate (884.54 mg, 6.40 mmol) and potassium iodide (5.31 mg, 32.00 μmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was extracted with 100.00 mL (50.00 mL x 2) of ethyl acetate. The combined organic phase was washed with 100.00 mL of saturated brine (50.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to furnish Compound 1-11.

[0133] Step K: 1-11 (1.00 g, 2.29 mmol) was dissolved in methanol (47.40 mL) followed by addition of sodium hydroxide solution (4 M, 10.32 mL). The reaction mixture was stirred at 25 °C for 20 min. The reaction mixture was quenched with hydrochloric acid (1 mol), the pH was adjusted to 3, and a solid was precipitated. The reaction mixture was extracted with 40.00 mL of ethyl acetate (20.00 mL x 2). The combined organic phase was washed with 30.00 mL of saturated sodium bicarbonate solution and 30.00 mL of saturated brine (15.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product. The crude product was subjected to thin layer chromatography (silica, petroleum ether: ethyl acetate = 0:1) to provide the compound of embodiment 1.

[0134] ee value (enantiomeric excess): 100%.

[0135] SFC (Supercritical Fluid Chromatography) Method: Column: Chiralcel OD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0136] 1H NMR (400 MHz, CDCl3) δ 15.67 (s, 1H), 8.50 (br s, 1H), 7.43 (s, 1H), 6.71 (s, 1H), 6 .67 (s, 1H), 4.19-4.40 (m, 2H), 4.10 (br t, J=6.11 Hz, 2H), 3.463.63 (m, 2H), 3.42 (s, 1H), 3.30 (s, 3H), 2.07 (quin, J=6.02 Hz, 2H), 1.77-1.98 (m, 2H), 0.96 (br s , 3H).

[0137] Modalities 2 to 5 can be prepared by the method relating to the preparation method of Modality 1: Modality 2

[0138] ee value (enantiomeric excess): 100%.

[0139] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0140] 1H NMR (400 MHz, CDCl3) δ 15.77 (br s, 1H), 8.49 (s, 1H), 7.52 (s, 1H), 6.87 (s, 1H), 6 .68 (s, 1H), 4.49-4.72 (m, 2H), 4.12-4.28 (m, 2H), 3.92 (br d, J=6.40 Hz, 1H) , 3.63 (t, J=5.90 Hz, 2H), 3.39 (s, 3H), 2.06-2.24 (m, 3H), 1.10 (d, J=6.53 Hz, 3H), 0.89 (d, J=6.53 Hz, 3H). Mode 3

[0141] ee value (enantiomeric excess): 100%.

[0142] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0143] 1H NMR (400 MHz, CDCl3) δ 15.81 (s, 1H), 8.88-9.18 (m, 1H), 7.47 (s, 1H), 6.78 (s, 1H ), 6.76 (s, 1H), 4.48-4.59 (m, 2H), 4.19 (dt, J=2.07, 6.12 Hz, 2H), 3.59-3, 67 (m, 2H), 3.45-3.52 (m, 1H), 3.39 (s, 3H), 2.15 (quin, J=6.05 Hz, 2H), 1.14-1 .31 (m, 2H), 0.29-0.55 (m, 2H), 0.09 (s, 1H). Mode 4

[0144] ee value (enantiomeric excess): 97%.

[0145] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0146] 1H NMR (400 MHz, CDCl3) δ 15.74 (s, 1H), 8.61 (br s, 1H), 7.52 (s, 1H), 6.79 (s, 1H), 6 .74 (s, 1H), 4.46 (br s, 2H), 4.20 (t, J=6.15 Hz, 2H), 4.04 (br s, 1H), 3.63 (dt, J=2.20, 5.87 Hz, 2H), 3.39 (s, 3H), 2.38 (br s, 1H), 2.16 (quin, J=5.96 Hz, 2H), 1 .60-2.00 (m, 6H), 1.09-1.25 (m, 2H). Mode 5

[0147] ee value (enantiomeric excess): 89%.

[0148] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0149] 1H NMR (400 MHz, CDCl3) δ = 15.73 (br s, 1H), 8.42 (s, 1H), 7.43 (s, 1H), 6.78 (s, 1H), 6.57 (s, 1H), 4.64 - 4.45 (m, 2H), 4.13 - 4.05 (m, 2H), 3.97 (ddd, J=2.4, 5.6 , 10.9 Hz, 1H), 3.53 (t, J=6.0 Hz, 2H), 3.30 (s, 3H), 2.06 (quin, J=6.1 Hz, 2H), 1.64 - 1.52 (m, 1H), 1.42 - 1.01 (m, 2H), 0.85 (t, J=7.4 Hz, 3H), 0.74 (d, J=6.6 Hz, 3H). Mode 6

[0150] Step A: Lithium aluminum tetrahydride (80.00 g, 2.11 mol, 2.77 eq) was added to a solution of 6-1 (100.00 g, 762.36 mmol, 1.00 eq) in tetrahydrofuran (400.00 mL) while maintaining the temperature below 0°C. The solution was stirred at 10°C for 10 h. Subsequently, 80.00 mL of water was added to the reaction mixture under stirring and 240.00 mL of 15% aqueous sodium hydroxide solution was added, followed by addition of 80.00 mL of water. The suspension was stirred at 10°C for 20 min, followed by filtration to afford a colorless liquid. The colorless liquid was concentrated under reduced pressure to afford compound 6-2.

[0151] 1H NMR (400 MHz, CDCl3) δ = 3.72 (dd, J=3.9, 10.2 Hz, 1H), 3.21 (t, J=10.2 Hz, 1H), 2 .51 (dd, J=3.9, 10.2 Hz, 1H), 0.91 (s, 9H).

[0152] Step B: 6-2 (50.00 g, 426.66 mmol) and triethylamine (59.39 mL, 426.66 mmol) were dissolved in dichloromethane (500.00 mL). Di-tert-butyl dicarbonate (92.19 g, 422.40 mmol) was dissolved in dichloromethane (100.00 mL) and was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was then stirred at 25 °C for 12 h. The reaction mixture was washed with saturated brine (600.00 mL), dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and rotary evaporated to dryness, followed by recrystallization with methyl tert-butyl ether/petroleum ether (50.00/100.00) to afford compound 6-3.

[0153] 1H NMR (400 MHz, CDCl3) δ 4.64 (br s, 1H), 3.80-3.92 (m, 1H), 3.51 (br d, J=7.09 Hz, 2H ), 2.17 (br s, 1H), 1.48 (s, 9H), 0.96 (s, 9H).

[0154] Step C: Thionyl chloride (100.98 mL, 1.39 mmol) was dissolved in acetonitrile (707.50 mL), 6-3 (121.00 g, 556.82 mmol) was dissolved in acetonitrile (282.90 mL) and added dropwise to the above reaction mixture at -40°C. After the addition was complete, pyridine (224.72 mL, 2.78 mol) was added to the reaction mixture in one portion. The ice bath was removed and the reaction mixture was stirred at 5 to 10°C for 1 h. After the solvent was rotary evaporated under reduced pressure to dryness, ethyl acetate (800.00 mL) was added and a solid precipitated. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to Further, the obtained oil, water and ruthenium chloride (12.55 g, 55.68 mmol) were dissolved in acetonitrile (153.80 mL). Sodium periodate (142.92 g, 668.19 mmol) was suspended in water (153.80 mL) and slowly added to the above reaction mixture. The final reaction mixture was stirred at 5 to 10 °C for 0.15 h. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (800.00 mLx2). The organic phase was washed with saturated brine (800.00 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, rotary evaporated under reduced pressure to dryness and purified by column chromatography (silica, petroleum ether/ethyl acetate = 50/1 to 20/1) to afford compound 6-4.

[0155] 1H NMR (400 MHz, CDCl3) δ 4.49-4.55 (m, 1H), 4.40-4.44 (m, 1H), 4.10 (d, J=6.15 Hz , 1H), 1.49 (s, 9H), 0.94 (s, 9H).

[0156] Step D: 6-5 (100.00 g, 657.26 mmol) was dissolved in acetonitrile (1300.00 mL), followed by addition of potassium carbonate (227.10 g, 1.64 mol) and 1-bromo-3-methoxypropane (110.63 g, 722.99 mmol). The reaction mixture was stirred at 85 °C for 6 h. The reaction solution was extracted with 600.00 mL of ethyl acetate (200.00 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 6-6.

[0157] 1H NMR (400 MHz, CDCl3) δ 9.76-9.94 (m, 1H), 7.42-7.48 (m, 2H), 6.98 (d, J=8.03 Hz , 1H), 4.18 (t, J=6.53 Hz, 2H), 3.95 (s, 3H), 3.57 (t, J=6.09 Hz, 2H), 3.33-3 .39 (m, 3H), 2.13 (quin, J=6.34 Hz, 2H).

[0158] Step E: 6-6 (70.00 g, 312.15 mmol) was dissolved in dichloromethane, followed by addition of m-chloroperoxybenzoic acid (94.27 g, 437.01 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled, followed by filtration, and the filtrate was extracted with dichloromethane. The organic phase was washed with 2000.00 mL of saturated sodium bicarbonate solution (400.00 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The brown oil was dissolved with as little methanol as possible, followed by slow addition of 2 M potassium hydroxide solution (350.00 mL) (the route was exothermic). The dark colored reaction mixture was stirred at room temperature for 20 min, and the pH of the reaction mixture was adjusted to 5 with 37% hydrochloric acid, followed by extraction with 400.00 mL of ethyl acetate (200.00 mL × 2). The organic phase was washed with water 200.00 mL of saturated brine (100.00 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Compound 6-7.

[0159] 1H NMR (400 MHz, CDCl3) δ 6.75 (d, J=8.53 Hz, 1H), 6.49 (d, J=2.89 Hz, 1H), 6.36 (dd, J=2.82, 8.60 Hz, 1H), 4.07 (t, J=6.40 Hz, 2H), 3.82 (s, 3H), 3.60 (t, J=6.15 Hz, 2H), 3.38 (s, 3H), 2.06-2.14 (m, 2H).

[0160] Step F: 6-7 (33.00 g, 155.48 mmol) was dissolved in tetrahydrofuran (330.00 mL), followed by addition of paraformaldehyde (42.02 g, 466.45 mmol), magnesium chloride (29.61 g, 310.97 mmol), and triethylamine (47.20 g, 466.45 mmol, 64.92 mL). The reaction mixture was stirred at 80 °C for 8 h. After completion of the reaction, the reaction mixture was quenched with 2 moles of hydrochloric acid solution (200.00 mL) at 25 °C and then extracted with 600.00 mL of ethyl acetate (200.00 mL x 3). The organic phase was washed with water 400.00 mL of saturated brine (200.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was washed with ethanol (30.00 mL) and filtered to give a filter residue, thereby yielding Compound 6-8.

[0161] 1H NMR (400 MHz, CDCl3) δ 11.29 (s, 1H), 9.55-9.67 (m, 1H), 6.83 (s, 1H), 6.42 (s, 1H ), 4.10 (t, J=6.48 Hz, 2H), 3.79 (s, 3H), 3.49 (t, J=6.05 Hz, 2H), 3.28 (s, 3H ), 2.06 (quin, J=6.27 Hz, 2H).

[0162] Step G: 6-8 (8.70 g, 36.21 mmol) was dissolved in N,N-dimethylformamide (80.00 mL), followed by addition of potassium carbonate (10.01 g, 72.42 mmol) and 6-4 (11.13 g, 39.83 mol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with 1.00 mol/L aqueous hydrochloric acid solution (200.00 mL) and extracted with ethyl acetate (150.00 mL × 2). The organic layers were combined, washed with water (150.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 6-9.

[0163] 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.34 (s, 1H), 6.57 (s, 1H), 4.18-4.26 (m, 3H ), 4.07 (dd, J=5.33, 9.60 Hz, 1H), 3.88 (s, 4H), 3.60 (t, J=5.96 Hz, 2H), 3.39 (s, 3H), 2.17 (quin, J=6.21 Hz, 2H), 1.47 (s, 9H), 1.06 (s, 9H).

[0164] Step H: 6-9 (15.80 g, 35.95 mmol) was dissolved in dichloromethane (150.00 mL) followed by addition of trifluoroacetic acid (43.91 mL, 593.12 mmol). The reaction mixture was stirred at 10 °C for 3 h. The reaction mixture was concentrated under reduced pressure and rotary evaporated to dryness, followed by addition of aqueous sodium bicarbonate solution (100.00 mL) and extraction with dichloromethane (100.00 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 6-10.

[0165] 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 6.80 (s, 1H), 6.51 (s, 1H), 4.30 (br d, J=12, 35 Hz, 1H), 4.04-4.11 (m, 3H), 3.79 (s, 3H), 3.49 (t, J=5.99 Hz, 2H), 3.36 (br d , J=2.93 Hz, 1H), 3.28 (s, 3H), 2.06 (quin, J=6.24 Hz, 2H), 1.02 (s, 9H).

[0166] Step I: 6-10 (5.00 g, 15.56 mmol) was dissolved in toluene (20.00 mL), followed by addition of 6-11 (8.04 g, 31.11 mmol). The reaction mixture was stirred at 120 °C for 12 h under a hydrogen atmosphere. The reaction mixture was quenched with water (100.00 mL) and extracted with ethyl acetate (100.00 mL x 2). The organic phases were combined, washed with water (80.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column and then purified by preparative high-performance liquid chromatography (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-70%, 25 min) to afford Compound 6-12.

[0167] 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 6.59 (s, 1H), 6.40 (s, 1H), 5.15-5.23 (m, 1H ), 4.35-4.41 (m, 2H), 4.08-4.19 (m, 2H), 3.94-4.00 (m, 2H), 3.72 (s, 3H), 3.61-3.67 (m, 1H), 3.46 (dt, J=1.96, 5.99 Hz, 2H), 3.27 (s, 3H), 3.01-3.08 ( m, 1H), 2.85-2.94 (m, 1H), 1.97-2.01 (m, 2H), 1.18-1.22 (m, 3H), 1.04 (s, 9H).

[0168] Step J: 6-12 (875.00 mg, 1.90 mmol) was dissolved in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), followed by addition of tetrachlorobenzoquinone (1.40 g, 5.69 mmol). The reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was cooled to room temperature, followed by addition of saturated sodium carbonate solution (50.00 mL) and ethyl acetate (60.00 mL). The mixture was stirred at 10 to 15 °C for 20 min and separated to give an organic phase. The organic phase was added to 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) and stirred at 10 to 15 °C for 20 min, followed by partition. The organic phase was washed with 2 mol/L aqueous hydrochloric acid solution (60.00 mL × 2), followed by partition. 2 mol/L aqueous sodium hydroxide solution (200.00 mL) and dichloromethane (200.00 mL) were added to the aqueous phase, followed by partition. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Compound 6-13.

[0169] 1H NMR (400 MHz, CDCl3) δ 7.98-8.78 (m, 1H), 6.86 (s, 1H), 6.43-6.73 (m, 2H), 4.41 -4.48 (m, 1H), 4.28-4.38 (m, 2H), 4.03-4.11 (m, 2H), 3.93 (br s, 1H), 3.80 (s, 3H), 3.47-3.52 (m, 3H), 3.29 (s, 3H), 2.06 (quin, J=6.24 Hz, 2H), 1.33 (t, J=7 .15Hz, 2H), 0.70-1.25 (m, 10H).

[0170] Step K: 6-13 (600.00 mg, 1.31 mmol) was dissolved in methanol (6.00 mL), followed by addition of 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 eq). The reaction mixture was stirred at 15 °C for 0.25 h. The pH of the reaction mixture was adjusted to 3 to 4 with 1.00 mol/L aqueous hydrochloric acid solution, followed by extraction with dichloromethane (50.00 mL x 3). The organic phases were combined, washed with saturated brine (50.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to furnish Embodiment 6.

[0171] ee value (enantiomeric excess): 100%.

[0172] SFC (Supercritical Fluid Chromatography) Method: Column: Chiralcel OD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0173] 1H NMR (400 MHz, CDCl3) δ 15.72 (br s, 1H), 8.32-8.93 (m, 1H), 6.60-6.93 (m, 2H), 6, 51 (br s, 1H), 4.38-4.63 (m, 2H), 4.11 (br dd, J=4.52, 12.23 Hz, 3H), 3.79-3.87 ( m, 3H), 3.46-3.54 (m, 2H), 3.29 (s, 3H), 2.07 (quin, J=6.24 Hz, 2H), 0.77-1.21 (m, 9H). Mode 7

[0174] Step A: 7-1 (50.00 g, 274.47 mmol, 1.00 eq) was dissolved in acetonitrile (500.00 mL) and cooled to 0 °C, followed by addition of chlorosuccinimide (37.75 g, 282.70 mmol, 1.03 eq). The mixture was heated to 25 °C and stirred for 10 h. Subsequently, the reaction mixture was concentrated under reduced pressure to give a colorless liquid, and ethyl acetate (500 mL) was added to the liquid. The solution was washed with water (100.00 mL*3) and saturated brine (100.00 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless liquid. The colorless liquid was purified by silica gel column to give 7-2.

[0175] Step B: Potassium carbonate (70.18 g, 507.80 mmol, 2.20 eq) was added to a solution of 7-2 (50.00 g, 230.82 mmol, 1.00 eq) and benzyl bromide (43.42 g, 253.90 mmol, 30.16 mL, 1.10 eq) in N,N-dimethylformamide (500.00 mL) in one portion. The mixture was then stirred at 25 °C for 10 h. Ethyl acetate (700.00 mL * 2) and water (200.00 mL) were added to the solution. The solution was stirred at 20 °C for 10 min. The organic phase was separated, washed with water (200.00 mL * 2) and saturated brine (200.00 mL * 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7-3.

[0176] Step C: Potassium hydroxide (6.00 mol/L, 41.57 mL, 3.06 eq) was added to a mixed solution of 7-3 (25.00 g, 81.50 mmol, 1.00 eq) in water (20.00 mL) and methanol (60.00 mL) in one portion. The solution was stirred at 50 °C for two hours. 50.00 mL of water was added to the solution. The solution was concentrated under reduced pressure to 70.00 mL and washed with petroleum ether/ethyl acetate (4/1, 20.00 mL * 2). The aqueous phase was separated and the pH was adjusted to 1-2 with 1.00 mol/L dilute hydrochloric acid to give a suspension. The suspension was filtered to give a white solid, which was then triturated with water (30.00 mL) to give 7-4.

[0177] Step D: Oxalyl chloride (17.35 g, 136.65 mmol, 11.96 mL, 2.00 eq) was added dropwise to a solution of 7-4 (20.00 g, 68.33 mmol, 1.00 eq) in dichloromethane (200.00 mL). The solution was stirred at 28 °C for two hours and then concentrated to afford 7-5.

[0178] Step E: A mixed solution of 7-5 (19.00 g, 61.06 mmol, 1.00 eq) and methylethyl-2-(dimethylaminomethylidene)-3-oxo-butanoate (11.88 g, 64.11 mmol, 1.05 eq) in tetrahydrofuran (50.00 mL) was added dropwise to a solution of lithium hexamethyldisilazide (1.00 mol/L, 152.65 mL, 2.50 eq) in tetrahydrofuran (10.00 mL) at -70°C over 5 min. The dry ice/acetone bath was removed and the solution was stirred for 5 min. Dilute hydrochloric acid (1.00 mol/L, 125.37 mL, 57.44 eq) was added to the mixture. The mixture was stirred vigorously and then rotary evaporated at 60 °C to remove most of the tetrahydrofuran. The residue was kept at 60 to 65 °C for 1.5 h. 200.00 mL of water was added to the mixture to give a suspension, which was stirred for 30 min and filtered to give a yellow solid. The yellow solid was further triturated with water (40.00 mL) and methyl tert-butyl ether (40.00 mL) to give Compound 7-6.

[0179] Step F: A mixed solution of 7-6 (10.00 g, 24.11 mmol, 1.00 eq) and valinol (3.73 g, 36.17 mmol, 4.01 mL, 1.50 eq) in acetic acid (30.00 mL) and ethanol (90.00 mL) was stirred at 90 °C for 10 h. The mixture was cooled to 20 °C and concentrated under reduced pressure at 40 °C to afford a yellow liquid. The yellow liquid was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1) to afford Compound 7-7.

[0180] Step G: Triethylamine (4.86 g, 48.06 mmol, 6.66 mL, 3.00 eq) was added to a solution of 7-7 (8.00 g, 15.36 mmol, 63.71%) in dichloromethane (10.00 mL) in one portion and methanesulfonyl chloride (3.67 g, 32.04 mmol, 2.84 mL, 2.00 eq) was then added to this. The solution was stirred at 20 °C for two hours. The solution was concentrated under reduced pressure to afford a brown residue. The residue was purified by silica gel chromatography (silica, petroleum ether/ethanol = 100/1 to 10/1) twice to afford Compound 7-8.

[0181] Step H: Palladium on carbon (1.00 g, 10%) was added to a solution of 7-8 (8.01 g, 13.86 mmol, 1.00 eq) in tetrahydrofuran (15.00 mL) under a nitrogen atmosphere. The suspension was then purged with hydrogen (2.80 g, 1.39 mol, 100.00 eq, 15 psi) several times. Afterwards, the mixture was then stirred at 15 °C for two hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a yellow gum, which was triturated with petroleum ether (30.00 mL * 2) and filtered to give Compound 7-9.

[0182] Step I: Potassium carbonate (0.45 g, 3.24 mmol, 2.00 eq) and potassium iodide (2.69 mg, 16.21 μmol, 0.01 eq) were added to a solution of 7-9 (0.79 g, 1.62 mmol, 1.00 eq) in N,N-dimethylformamide (4.00 mL). The resulting mixture was stirred at 100 °C for 10 h. The solution was then poured into 10.00 mL of water and extracted with ethyl acetate (30.00 mL*2). The organic phases were combined, washed with water (5.00 mL*3) and saturated brine (5.00 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to furnish Compound 7-10.

[0183] Step J: Boron tribromide (1.15 g, 4.59 mmol, 442.31 μL, 6.00 eq) was added dropwise to a solution of 7-10 (300.00 mg, 765.62 μmol, 1.00 eq) in dichloromethane (30.00 mL) while maintaining the temperature below -78°C. After the addition was complete, the solution was stirred between -78°C and 0°C for 10 h. The reaction solution was quenched with MeOH and concentrated under reduced pressure to afford a yellow liquid. A dichloromethane/methanol (10/1, 100.00 mL) solution was added to the yellow liquid. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Compound 7-11.

[0184] Step K: Thionyl chloride (687.08 mg, 5.78 mmol, 418.95 μL, 10.00 eq) was added to a solution of 7-11 (202.00 mg, 577.52 μmol, 1.00 eq) in methanol (21.18 g, 661.15 mmol, 26.81 mL, 1144.80 eq) under a nitrogen atmosphere in one portion. The mixture was stirred at 50 °C for 4 h. The reaction mixture was concentrated under reduced pressure to furnish Compound 7-12.

[0185] Step L: 7-12 (70.00 mg, 192.22 μmol) was dissolved in N,N-dimethylformamide (2.00 mL), followed by addition of potassium carbonate (34.57 mg, 250.15 μmol) and 2-chloroethyl sulfide (31.18 mg, 250.15 μmol). The mixture was stirred at 100 °C for 12 h to afford 7-13. The reaction mixture was used directly in the next step without purification.

[0186] Step M: 7-13 (86.97 mg, 192.43 μmol) was dissolved in water (1.00 mL), and potassium carbonate (26.59 mg, 192.43 μmol) was added thereto. The mixture was stirred at 100 °C for 12 hours. The pH of the reaction mixture was adjusted to 3-4, and the reaction mixture was purified by preparatory high performance liquid chromatography (column: Boston Green ODS 150*30 4 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 55%-85%, 10.5 minutes) to afford Embodiment 7.

[0187] ee value (enantiomeric excess): 100%.

[0188] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0189] 1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 1H), 7.75 (s, 1H), 7.03 (s, 1H), 6.92 (s, 1H), 4 .71 (br s, 2H), 4.55 (br d, J=9.2 Hz, 1H), 4.34 - 4.25 (m, 2H), 2.92 (t, J=6.3 Hz, 2H), 2.67 (q, J=7.3 Hz, 2H), 1.83 (br s, 1H), 1.21 (t, J=7.4 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.5 Hz, 3H).

[0190] Embodiment 8 can be prepared by the method relating to the method of preparing Embodiment 7: Embodiment 8

[0191] ee value (enantiomeric excess): 100%.

[0192] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pad AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0193] 1H NMR (400MHz, DMSO-d6) δ 8.79 (s, 1H), 7.76 (s, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 4 .71 (br s, 2H), 4.55 (br d, J=10.7 Hz, 1H), 4.35 - 4.27 (m, 2H), 2.90 (t, J=6.3 Hz, 2H), 2.20 (s, 3H), 2.08 (s, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.5 Hz, 3H). Mode 9

[0194] Compound 9-5 can be prepared by the method related to the method of preparing Compound 7-12:

[0195] Step A: 9-1 (5.00 g, 54.25 mmol) was dissolved in N,N-dimethylformamide (20.00 mL), followed by addition of diisopropylethylamine (10.52 g, 81.38 mmol) and benzyl 2-bromoacetate (12.43 g, 54.25 mmol). The mixture was stirred at 15 °C for 16 h. The reaction mixture was filtered to give a filtrate, followed by addition of water (50.00 mL) and extraction with ethyl acetate (50.00 mL * 2). The combined organic phases were washed with saturated brine (30.00 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give Compound 9-2.

[0196] 1H NMR (400MHz, CDCl3) δ 7.24-7.32 (m, 5H), 5.10 (s, 2H), 3.64 (br d, J=3.06 Hz, 2H), 3.21 (s, 2H), 2.66 (t, J=7.09 Hz, 2H), 1.70-1.80 (m, 2H).

[0197] Step B: 9-2 (5.00 g, 20.81 mmol) was dissolved in dichloromethane (50.00 mL), followed by addition of triethylamine (3.16 g, 31.22 mmol) and methanesulfonyl chloride (2.62 g, 22.89 mmol). The mixture was stirred at 10 °C for 3 h. The reaction solution was used directly in the next step without purification. The reaction mixture was quenched with water (50.00 mL) and extracted with dichloromethane (50.00 mL * 2). The combined organic phases were then washed with water (50.00 mL) and saturated brine (50.00 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford Compound 9-3.

[0198] 1H NMR (400MHz, CDCl3) δ 7.34-7.42 (m, 5H), 5.20 (s, 2H), 4.31 (t, J=6.09 Hz, 2H), 3 .29 (s, 2H), 3.02 (s, 3H), 2.76 (t, J=7.03 Hz, 2H), 1.99-2.07 (m, 2H).

[0199] Step C: 9-3 (91.90 mg, 288.63 μmol) was dissolved in N,N-dimethylformamide (2.00 mL), followed by addition of potassium carbonate (45.21 mg, 327.11 μmol). The mixture was stirred at 70 °C for 12 h to afford 9-4. The reaction mixture was used directly in the next step without purification.

[0200] Step D: 9-4 (112.78 mg, 192.43 μmol) was dissolved in water (2.00 mL), and potassium carbonate (26.59 mg, 192.43 μmol) was added thereto. The mixture was stirred at 100 °C for 12 hours. The pH of the reaction mixture was adjusted to 3 to 4, and the reaction mixture was purified by preparatory high performance liquid chromatography (column: Boston Green ODS 150*25 10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 30%-60%, 11 minutes) to afford Embodiment 9.

[0201] ee value (enantiomeric excess): 81.8%.

[0202] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0203] 1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 1H), 7.75 (s, 1H), 7.02 (s, 1H), 6.90 (s, 1H), 4 .70 (br s, 2H), 4.55 (br d, J=10.3 Hz, 1H), 4.27 - 4.11 (m, 2H), 3.27 (s, 2H), 2, 76 (t, J=7.2 Hz, 2H), 2.07 - 1.97 (m, 2H), 1.84 (br s, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.71 (br d, J=6.4 Hz, 3H). Mode 10

[0204] Compound 10-1 can be prepared by the method related to the method of preparing Compound 7-12:

[0205] Step A: 10-1 (700.00 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (20.00 mL), followed by addition of potassium carbonate (452.09 mg, 3.27 mmol) and 3-bromo-1-propanol (401.13 mg, 2.89 mmol). The mixture was stirred at 50 °C for 5 h, followed by addition of water (45.00 mL) and extraction with 150.00 mL (50.00 mL * 3) of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product. The crude product was purified by preparatory high-performance liquid chromatography (column: Boston Green ODS 250*50 mm, 10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 15%-45%; 30 min) to afford Compound 10-2.

[0206] 1H NMR (400MHz, CDCl3) δ 8.21 (s, 1H), 7.53 (s, 1H), 6.73 (s, 1H), 6.64 (s, 1H), 4.68 - 4.46 (m, 2H), 4.28 - 4.20 (m, 2H), 3.95 (s, 3H), 3.73 (ddd, J=2.9, 5.3, 10, 9 Hz, 1H), 2.15 (quin, J=5.8 Hz, 2H), 2.10 - 2.03 (m, 1H), 1.28 (s, 2H), 1.08 (d, J=6.5Hz, 3H), 0.90 (d, J=6.5Hz, 3H).

[0207] Step B: 10-2 (100.00 mg, 237.04 μmol) was dissolved in dichloromethane (20.00 mL), and Dess-Martin oxidant (110.59 mg, 260.74 μmol) was added at 0 °C. The mixture was stirred at 20 °C for 2 hours. Saturated sodium bicarbonate (20.00 mL) and sodium thiosulfate (20.00 mL) were added thereto, followed by filtration to give a filtrate. The organic phase was washed with saturated sodium bicarbonate (20.00 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to afford Compound 10-3.

[0208] Step C: 10-3 (40.00 mg, 95.27 μmol) and methoxylamine hydrochloride (9.55 mg, 114.33 μmol) were dissolved in dichloromethane (10.00 mL), and pyridine (9.04 mg, 114.33μmol) was added thereto. The mixture was stirred at 15 °C for 12 h, rotary evaporated to remove the solvent, followed by dilution with 15.00 mL of water and extraction with 30.00 mL of ethyl acetate (10.00 mL*3). The combined organic phases were then dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford a crude product. The crude product was purified by silica gel plate (eluent: dichloromethane/methanol = 10/1) to afford Compound 10-4.

[0209] Step D: 10-4 (30.00 mg, 66.30 μmol) was dissolved in methanol (9.00 mL), and sodium hydroxide solution (4.00 mol, 3.00 mL) was added. The mixture was stirred at 15 °C for 0.5 hour. The pH of the reaction mixture was adjusted to 3-4, and the reaction mixture was purified by preparatory high performance liquid chromatography (column: Boston Green ODS 150*30 4 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 50%-74%, 10.5 minutes) to furnish Embodiment 10.

[0210] ee value (enantiomeric excess): 5.8%.

[0211] SFC Method (Supercritical Fluid Chromatography): Column: Chiral OD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0212] 1H NMR (400MHz, DMSO-d6) δ 8.77 (br s, 1H), 7.74 (br s, 1H), 7.49 (t, J=5.8 Hz, 1H), 7 .01 (br s, 1H), 6.94 - 6.86 (m, 1H), 4.69 (br s, 2H), 4.54 (br s, 1H), 4.36 - 4.20 ( m, 2H), 3.83 - 3.71 (m, 3H), 2.78 - 2.61 (m, 2H), 1.83 (br s, 1H), 0.98 (d, J=6 .4 Hz, 3H), 0.71 (br d, J=6.4 Hz, 3H). Modality 11

[0213] Compound 11-1 can be prepared by the method related to the method of preparing Compound 7-12:

[0214] Step A: 11-1 (700.00 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (20.00 mL), followed by addition of potassium carbonate (452.09 mg, 3.27 mmol) and 3-bromo-1-propanol (401.13 mg, 2.89 mmol). The mixture was stirred at 50 °C for 5 h, followed by addition of water (45.00 mL) and extraction with 150.00 mL (50.00 mL * 3) of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product. The crude product was purified by preparatory high-performance liquid chromatography (column: Boston Green ODS 250*50 mm, 10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 15%-45%; 30 min) to afford Compound 11-2.

[0215] 1H NMR (400MHz, CDCl3) δ 8.21 (s, 1H), 7.53 (s, 1H), 6.73 (s, 1H), 6.64 (s, 1H), 4.68 - 4.46 (m, 2H), 4.28 - 4.20 (m, 2H), 3.95 (s, 3H), 3.73 (ddd, J=2.9, 5.3, 10, 9 Hz, 1H), 2.15 (quin, J=5.8 Hz, 2H), 2.10 - 2.03 (m, 1H), 1.28 (s, 2H), 1.08 (d, J=6.5Hz, 3H), 0.90 (d, J=6.5Hz, 3H).

[0216] Step B: 11-2 (80.00 mg, 189.63 mmol), 4-dimethylaminopyridine (231.67 μg, 1.90 μmol), and triethylamine (57.57 mg, 568.89 μmol) were dissolved in dichloromethane (20.00 mL), followed by addition of methylaminoformyl chloride (35.47 mg, 379.26 mol). The mixture was stirred at 15 °C for 5 h, followed by addition of water (15.00 mL) and extraction with 45.00 mL (15.00 mL * 3) of dichloromethane. The combined organic phases were then dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford Compound 11-3.

[0217] Step C: 11-3 (90.00 mg, 187.92 μmol) was dissolved in methanol (10.00 mL), tetrahydrofuran (10.00 mL), and water (10.00 mL), and lithium hydroxide monohydrate (23.66 mol, 563.77 μmol) was added. The mixture was stirred at 20 °C for 12 h. The pH of the reaction mixture was adjusted to 3 to 4, the reaction mixture was diluted with 20.00 mL of water, and extracted with 45.00 mL (15.00 mL * 3) of dichloromethane. The combined organic phases were then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product. The crude product was purified by preparatory high-performance liquid chromatography (column: Boston Green ODS 150*30 4 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-65%; 10.5 min) to furnish Mode 11.

[0218] ee value (enantiomeric excess): 100%.

[0219] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0220] 1H NMR (400MHz, DMSO-d6) δ 8.79 (s, 1H), 7.76 (s, 1H), 7.11 - 6.95 (m, 2H), 6.89 (s, 1H), 4.71 (br s, 2H), 4.56 (br d, J=7.5 Hz, 1H), 4.23 - 4.07 (m, 4H), 2.56 (d, J =4.5Hz, 3H), 2.08 - 2.02 (m, 2H), 1.96 - 1.71 (m, 1H), 0.98 (d, J=6.5Hz, 3H) , 0.71 (br d, J=6.5 Hz, 3H). Mode 12

[0221] Compound 12-1 can be prepared by the method relating to the method of preparing Compound 7-12:

[0222] Step A: 12-1 (100.00 mg, 274.88 μmol) was dissolved in N,N-dimethylformamide (2.00 mL), followed by addition of potassium carbonate (49.39 mg, 357.34 μmol) and 4-bromobutyl tert-butyl ester (79.73 mg, 357.34 μmol). The mixture was stirred at 100 °C for 12 h, followed by addition of water (30.00 mL) and extraction with 45.00 mL (15.00 mL * 3) of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford a crude product 12-2.

[0223] Step B: 12-2 (128.00 mg, 252.97 μmol) was dissolved in dichloromethane (3.00 mL), followed by addition of trifluoroacetic acid (4.62 mg, 40.52 μmol). The mixture was stirred at 15 °C for 1 h and rotary evaporated to remove the solvent and afford a crude product 12-3.

[0224] Step C: 12-3 (80.00 mg, 177.83 μmol) was dissolved in dichloromethane (10.00 mL), followed by addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (81.14 mg, 213.39 μmol) and triethylamine (26.99 mg, 266.74 μmol). The mixture was stirred at 25 °C for 30 min, followed by addition of diethylamine (15.61 mg, 213.39 μmol). The mixture was stirred at 25 °C for 12 h, followed by addition of water (20.00 mL) and extraction with 45.00 mL (15.00 mL *3) of dichloromethane. The combined organic phases were then dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 12-4.

[0225] Step D: 12-4 (80.00 mg, 158.22 μmol) was dissolved in methanol (4.50 mL), and sodium hydroxide solution (4.00 mol, 1.71 mL) was added. The mixture was stirred at 20 °C for 5 min. The pH of the reaction mixture was adjusted to 2 to 3, and the reaction mixture was purified by preparatory high performance liquid chromatography (column: Boston Green ODS 150*25mm, 10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 40%-70%, 11 min) to furnish Embodiment 12.

[0226] ee value (enantiomeric excess): 99.5%.

[0227] SFC (Supercritical Fluid Chromatography) Method: Column: Chiralcel OD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0228] 1H NMR (00MHz, DMSO-d6) δ 8.77 (br s, 1H), 7.74 (s, 1H), 7.12 - 6.79 (m, 2H), 4.77 - 4 .48 (m, 1H), 4.80 - 4.45 (m, 2H), 4.22 - 4.10 (m, 2H), 3.29 (br dd, J=7.0, 11.7 Hz, 4H), 2.49 - 2.45 (m, 2H), 1.98 (quin, J=6.6 Hz, 2H), 1.82 (br s, 1H), 1.10 (t, J=7.1 Hz, 3H), 1.04 - 0.96 (m, 6H), 0.71 (br d, J=6.4 Hz, 3H). Mode 13

[0229] Compound 13-5 can be prepared by the method related to the method of preparing Compound 7-12:

[0230] Step A: A mixture of 13-1 (13.20 g, 150.00 mmol), 2,2,2,-trifluoroethanol (10.00 g, 99.96 mmol), triethylamine (10.11 g, 100.00 mmol), and tetrabutylammonium iodide (738.24 mg, 2.00 mmol) was purged with nitrogen gas. The mixture was stirred at 100 °C for 24 h. The reaction mixture was distilled to afford Compound 13-2.

[0231] 1H NMR (400MHz, CDCl3) δ 3.91 (q, J=8.74 Hz, 2H), 3.72-3.82 (m, 4H), 2.21 (br s, 1H).

[0232] Step B: 13-2 (1.00 g, 6.94 mmol) was dissolved in dichloromethane (15.00 mL) and triethylamine (912.94 mg, 9.02 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (1.15 g, 10.04 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was used directly in the next step without purification. The reaction mixture was quenched with saturated sodium carbonate (20.00 mL), diluted with water (10.00 mL), extracted with 60.00 mL (20.00 mL * 3) of dichloromethane, dried over anhydrous sodium sulfate, and distilled under reduced pressure to afford Compound 13-3.

[0233] 1H NMR (400MHz, CDCl3) δ 4.43 - 4.39 (m, 2H), 3.96 - 3.88 (m, 4H), 3.07 (s, 3H).

[0234] Step C: 13-3 (85.50 mg, 384.84 μmol) was dissolved in N,N-dimethylformamide (2.00 mL), followed by addition of potassium carbonate (53.19 mg, 384.84 μmol). The mixture was stirred at 100 °C for 12 h to afford 13-4. The reaction mixture was used directly in the next step without purification.

[0235] Step D: 13-4 (94.26 mg, 192.22 μmol) was dissolved in water (0.50 mL), and the mixture was stirred at 100 °C for 12 h. The pH of the reaction mixture was adjusted to 3-4, and the reaction mixture was purified by preparatory high-performance liquid chromatography (column: Boston Green ODS 150*30 4 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 50%-80%, 10.5 min) to furnish Embodiment 13.

[0236] ee value (enantiomeric excess): 83.8%.

[0237] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0238] 1H NMR (400MHz, DMSO-d6) δ 8.76 (s, 1H), 7.75 (s, 1H), 6.99 (br s, 1H), 6.92 (s, 1H), 4.75 - 4.63 (m, 2H), 4.53 (br d, J=9.8 Hz, 1H), 4.36 - 4.27 (m, 2H), 4.19 (q, J =9.3 Hz, 2H), 3.98 (t, J=4.2 Hz, 2H), 1.93 - 1.74 (m, 1H), 0.98 (d, J=6.4 Hz , 3H), 0.71 (d, J=6.5 Hz, 3H).

[0239] Embodiments 14 to 21 can be prepared by the method relating to the preparation method of Embodiment 7: Embodiment 14

[0240] ee value (enantiomeric excess): 67.6%.

[0241] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0242] 1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 1H), 7.75 (s, 1H), 7.02 (s, 1H), 6.89 (s, 1H), 4 .71 (br d, J=3.4 Hz, 2H), 4.55 (br d, J=10.4 Hz, 1H), 3.92 (s, 3H), 1.91 - 1.71 ( m, 1H), 0.99 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.5 Hz, 3H). Mode 15

[0243] ee value (enantiomeric excess): 100%.

[0244] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0245] 1H NMR (400MHz, DMSO-d6) δ 8.76 (br s, 1H), 7.73 (s, 1H), 7.11 - 6.75 (m, 2H), 4.73 - 4 .47 (m, 3H), 3.98 (dd, J=4.7, 6.8 Hz, 2H), 1.99 - 1.67 (m, 1H), 1.32 - 1.22 (m , 1H), 0.97 (d, J=6.5 Hz, 3H), 0.71 (br d, J=6.5 Hz, 3H), 0.60 (br dd, J=1.5, 7.9 Hz, 2H), 0.37 (q, J=4.5 Hz, 2H). Modality 16

[0246] ee value (enantiomeric excess): 100%.

[0247] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0248] 1H NMR (400MHz, DMSO-d6) δ 8.76 (s, 1H), 7.73 (s, 1H), 6.99 (br s, 1H), 6.87 (s, 1H), 4.69 (br d, J=2.9 Hz, 2H), 4.53 (br d, J=11.3 Hz, 1H), 3.90 (dd, J=2.7, 6.5 Hz , 2H), 2.10 - 2.04 (m, 1H), 1.92 - 1.75 (m, 1H), 1.01 (d, J=6.7 Hz, 6H), 0.98 ( d, J=6.5 Hz, 3H), 0.71 (d, J=6.5 Hz, 3H). Modality 17

[0249] ee value (enantiomeric excess): 100%.

[0250] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0251] 1H NMR (400MHz, DMSO-d6) δ 8.76 (s, 1H), 7.73 (s, 1H), 6.98 (br s, 1H), 6.89 (s, 1H), 4.71 - 4.49 (m, 3H), 4.00 (br d, J=5.7 Hz, 2H), 3.91 - 3.87 (m, 2H), 3.35 (br s, 2H), 2.12 - 2.01 (m, 2H), 1.73 - 1.62 (m, 2H), 1.43 - 1.32 (m, 2H), 0.98 (br d, J =6.5 Hz, 3H), 0.71 (br d, J=6.5 Hz, 3H). Modality 18

[0252] ee value (enantiomeric excess): 100%.

[0253] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0254] 1H NMR (400MHz, DMSO-d6) δ 8.76 (br s, 1H), 7.74 (s, 1H), 7.16 - 6.83 (m, 2H), 4.70 (br s, 2H), 4.52 (br s, 1H), 4.31 - 4.21 (m, 2H), 3.70 (t, J=4.4 Hz, 2H), 3.34 (s, 3H), 1.94 - 1.68 (m, 1H), 0.98 (d, J=6.4 Hz, 3H), 0.71 (d, J=6.5 Hz, 3H). Modality 19

[0255] ee value (enantiomeric excess): 100%.

[0256] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0257] 1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 1H), 7.74 (s, 1H), 7.01 (br s, 1H), 6.88 (s, 1H), 4.70 (br d, J=2.4 Hz, 2H), 4.55 (br d, J=8.9 Hz, 1H), 4.21 - 4.06 (m, 2H), 3.40 (br s, 2H), 3.24 (s, 3H), 1.90 - 1.72 (m, 3H), 1.71 - 1.63 (m, 2H), 0.98 (d, J= 6.5 Hz, 3H), 0.71 (br d, J=6.5 Hz, 3H). Modality 20

[0258] ee value (enantiomeric excess): 100%.

[0259] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0260] 1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 1H), 7.76 (s, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 4 .70 (br d, J=2.8 Hz, 2H), 4.55 (br d, J=8.4 Hz, 1H), 4.30 - 4.23 (m, 2H), 4.21 - 4.11 (m, 2H), 3.69 - 3.50 (m, 2H), 3.35 - 3.33 (m, 2H), 2.00 (quin, J=6.4 Hz, 2H) , 1.94 - 1.73 (m, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.71 (br d, J=6.5 Hz, 3H). Modality 21

[0261] ee value (enantiomeric excess): 100%.

[0262] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0263] 1H NMR (400MHz, DMSO-d6) δ 8.78 (s, 1H), 7.76 (s, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 4 .70 (br d, J=3.1 Hz, 2H), 4.55 (br d, J=10.0 Hz, 1H), 4.29 - 4.20 (m, 4H), 2.18 ( quin, J=6.0 Hz, 2H), 1.83 (br s, 1H), 0.98 (d, J=6.4 Hz, 3H), 0.71 (d, J=6.5 Hz , 3H). Modality 22

[0264] Compound 22-1 can be prepared by the method related to the method of preparing Compound 7-12:

[0265] Step A: Potassium carbonate (182.36 mg, 1.32 mmol, 1.60 eq) was added to a solution of 22-1 (300.00 mg, 824.65 μmol, 1.00 eq) and 5-bromo-2-pentanone (176.92 mg, 1.07 mmol, 1.30 eq) in N,N-dimethylformamide (3.00 mL) in one portion. The solution was stirred at 110 °C for 10 h and 1.00 mol/L dilute hydrochloric acid (5.00 mL) was added. The mixture was stirred at 10 °C for 10 min and extracted with ethyl acetate (30.00 mL * 3). The combined organic phases were washed with water (10.00 mL* 3) and saturated brine (10.00 mL* 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid, which was separated by silica gel plate chromatography (dichloromethane/methanol 10/1) (twice) to give Compound 22-2.

[0266] Step B: 4 mol/L sodium hydroxide aqueous solution (0.50 mL) was added to a solution of 22-2 (50.00 mg, 111.63 μmol, 1.00 eq) in methanol (3.00 mL) in one portion. The mixed solution was stirred at 40 °C for 10 min, followed by the addition of 1.00 mL of 1.00 mol/L dilute aqueous hydrochloric acid solution and concentration under reduced pressure to afford a yellow solid. The yellow solid was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini 150 mm * 25 mm * 10 μm; mobile phase: [water (0.05% ammonia) - acetonitrile]; elution gradient: 9% - 39%, 10 min) to afford Embodiment 22.

[0267] ee value (enantiomeric excess): 93%.

[0268] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0269] 1H NMR (400MHz, CD3OD) δ = 8.43 (br s, 1H), 7.57 (br s, 1H), 6.84 - 6.67 (m, 2H), 4.75 - 4 .51 (m, 2H), 4.13 (br d, J=5.6 Hz, 3H), 2.75 (br t, J=6.8 Hz, 2H), 2.20 (s, 3H) , 2.13 - 2.08 (m, 2H), 1.95 (br s, 1H), 1.07 (br d, J=6.2 Hz, 3H), 0.82 (br d, J= 6.0Hz, 3H). Modality 23

[0270] Compound 23-1 can be prepared by the method related to the method of preparing Compound 7-12:

[0271] Step A: Potassium carbonate (121.57 mg, 879.63 μmol, 1.60 eq) was added to a solution of 23-1 (200.00 mg, 549.77 μmol, 1.00 eq) in N,N-dimethylformamide (8.00 mL). The solution was stirred at 110 °C for 1 h. 3.00 mL of water was added to the solution and the suspension was filtered to provide a brown solid. The brown solid was separated by preparative silica gel plate (dichloromethane/methanol 10/1) twice to provide Compound 23-2.

[0272] Step B: Trifluoroacetic acid (950.29 mg, 8.33 mmol, 617.07 μL, 48.91 eq) was added dropwise to a solution of 23-2 (84.00 mg, 170.40 μmol, 1.00 eq) in dichloromethane (2.00 mL). The resulting solution was stirred at 10 °C for three minutes and concentrated under reduced pressure to afford Compound 23-3.

[0273] Step C: Methyl chloroformate (37.16 mg, 393.26 μmol, 30.46 μL, 2.00 eq) was added dropwise slowly to a solution of 23-3 (80.00 mg, 196.63 μmol, 1.00 eq) and triethylamine (50.74 mg, 501.41 μmol, 69.50 μL, 2.55 eq) in dichloromethane (2.00 mL) at 0 °C under a nitrogen atmosphere within 5 min. The resulting solution was stirred at 0 to 14°C for 30 min, and separated by high-performance liquid chromatography (column: Phenomenex Synergi C18 150 mm * 25 mm * 10 μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; elution gradient: 33% - 53%, 10 min) to afford Mode 23.

[0274] ee value (enantiomeric excess): 100%.

[0275] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0276] 1H NMR (400MHz, CDCl3) δ = 15.61 (br s, 1H), 8.38 (br s, 1H), 7.45 (s, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 5.08 (br s, 1H), 4.65 - 4.45 (m, 2H), 4.07 (br s, 2H), 3.79 (br s, 1H ), 3.61 (s, 3H), 3.39 (br d, J=5.1 Hz, 2H), 2.04 (br s, 2H), 1.18 (s, 1H), 1.02 (br d, J=5.9 Hz, 3H), 0.81 (br d, J=6.1 Hz, 3H). Mode 24

[0277] Compound 24-4 can be prepared by the method relating to the method of preparing Compound 6-4:

[0278] Step A: 24-5 (100.00 g, 724.01 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (600.00 mL). After cooling to 0 °C, potassium carbonate (100.06 g, 724.01 mmol, 1.00 eq) was added. After heating the mixture to 90 °C, 1-bromo-3-methoxy-propane (110.79 g, 724.01 mmol, 1.00 eq) in N,N-dimethylformamide (400.00 mL) was slowly added to the solution within 1 hour. The mixed solution was further stirred at 90 °C for one hour. The solution was then poured into 400.00 mL of water and extracted with ethyl acetate (800.00 mL*3). The organic phases were combined, washed with water (500.00 mL) and saturated brine (200.00 mL * 2), concentrated under reduced pressure to give a white solid, and purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/1 to 80/1) to give Compound 24-6.

[0279] Step B: 24-6 (50.00 g, 237.84 mmol, 1.00 eq) was dissolved in acetonitrile (300.00 mL) and cooled to 0 °C, followed by addition of chlorosuccinimide (32.08 g, 240.22 mmol, 1.01 eq). The mixture was heated to 25 °C and stirred for 10 h. The solution was concentrated under reduced pressure to afford a colorless liquid. 500 mL of ethyl acetate was poured into the liquid, and the mixture was washed with water (100.00 mL*3) and saturated brine (100.00 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a white solid. The obtained white solid was triturated with methanol to afford Compound 24-7.

[0280] Step C: Potassium carbonate (21.59 g, 156.21 mmol, 2.00 eq) was added to a solution of 24-7 (19.11 g, 78.10 mmol, 1.00 eq) and 24-4 (24.00 g, 85.91 mmol, 1.10 eq) in N,N-dimethylformamide (300.00 mL) in one portion. The solution was stirred at 50 °C for two hours. The reaction mixture was poured into 100.00 mL of water and extracted with ethyl acetate (1000.00 mL). The organic phase was separated, washed with water (100.00 mL) and saturated brine (100.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to furnish Compound 24-8.

[0281] Step D: Trifluoroacetic acid (68.68 g, 602.31 mmol, 44.59 mL, 8.10 eq) was added to a solution of 24-8 (33.00 g, 74.33 mmol, 1.00 eq) in dichloromethane (30.00 mL) in one portion. The solution was stirred at 10 °C for 1 h and concentrated under reduced pressure to provide a brown oil. 100.00 mL of aqueous sodium bicarbonate solution was added, then the mixture was stirred at 10 °C for 1 h and extracted with 600.00 mL of ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to provide Compound 24-9.

[0282] Step E: 24-9 (10.00 g, 30.69 mmol, 1.00 eq) was added to a solution of 24-11 (15.86 g, 61.38 mmol, 2.00 eq) in toluene (100.00 mL) in one portion. After purging the suspension with nitrogen gas several times, it was heated to 120 °C and stirred for 28 h. The solution was concentrated under reduced pressure to afford a brown oil. The brown oil was subjected to silica gel column chromatography (ISCO®; 330 g SepaFlash® silica gel flash column, 5% trifluoroacetic acid/acetonitrile as eluent, flow rate: 100 mL/min) to afford Compound 24-10.

[0283] Step F: A solution of 24-10 (4.20 g, 9.01 mmol, 1.00 eq) and tetrachlorobenzoquinone (5.54 g, 22.53 mmol, 2.50 eq) in toluene (60.00 mL) and glycol dimethyl ether (60.00 mL) was stirred at 120 °C for 2 h. The solution was concentrated under reduced pressure to afford a brown oil. The brown oil was subjected to flash chromatography on a silica gel column (ISCO®; 330 g SepaFlash® silica gel flash column, mobile phase: 0-70% acetonitrile/5% trifluoroacetic acid, flow rate: 100 mL/min) to afford a brown oil. The residue was subjected to high-performance liquid column chromatography (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 38%-68%, 30 min) to afford Mode 24.

[0284] ee value (enantiomeric excess): 100%.

[0285] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0286] 1H NMR (400MHz, CDCl3) δ = 9.04 - 8.37 (m, 1H), 7.66 - 7.51 (m, 1H), 7.07 - 6.54 (m, 2H) , 4.90 - 4.48 (m, 2H), 4.18 (br s, 3H), 3.62 (br s, 2H), 3.39 (s, 3H), 2.15 (quin, J =5.9Hz, 2H), 1.30 - 0.91 (m, 9H). Mode 25

[0287] Compound 25-4 can be prepared by the method relating to the method of preparing Compound 6-4:

[0288] Step A: A mixture of 25-1 (140.00 g, 1.01 mol), potassium carbonate, and N,N-dimethylformamide (500.00 mL) was heated at 90 °C for 1 h. A solution of 1-bromo-3-methoxy-propanol (147.34 g, 962.93 mmol) in N,N-dimethylformamide (100.00 mL) was then added dropwise to the mixture at 90 °C, and then stirred at 90 °C for 5 h. The mixture was poured into water (1500.00 mL) and extracted with ethyl acetate (1000.00 mL*2). The organic phases were combined, washed with saturated brine (1000.00 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to afford a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 10/1) to afford Compound 25-2.

[0289] Step B: A solution of bromine (33.34 g, 208.65 mmol, 10.76 mL) in dichloromethane (100.00 mL) was added dropwise to a solution of 252 (40.00 g, 189.68 mmol) in dichloromethane (300.00 mL) at 0 °C under a nitrogen atmosphere. After stirring the mixture at 15 °C for 1 h, it was quenched with saturated sodium thiosulfate solution (200.00 mL) and extracted with ethyl acetate (100.00 mL*2). The organic phases were combined, washed with saturated brine (100.00 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to afford Compound 25-3.

[0290] 1H NMR (400MHz, CDCl3) δ = 11.43 (s, 1H), 9.78 - 9.63 (m, 1H), 7.69 (s, 1H), 6.50 (s, 1H ), 4.20 (t, J=6.1 Hz, 2H), 3.73 - 3.52 (m, 2H), 3.39 (s, 3H), 2.23 - 2.08 (m, 2H).

[0291] Step C: Potassium carbonate (26.77 g, 193.69 mmol) and 25-4 were added to a solution of 25-3 (28.20 g, 96.84 mmol) in dimethylformamide (280.00 mL) at 15 °C. The mixture was stirred at 50 °C for 2 h. The mixture was poured into saturated aqueous ammonium chloride solution (300.00 mL) and extracted with ethyl acetate (200.300 mL*2). The organic phase was washed with saturated brine (100.00 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to afford Compound 25-5.

[0292] Step D: Trifluoroacetic acid (229.01 g, 2.01 mol, 148.71 mL) was added to a solution of 25-5 (45.00 g, 91.34 mmol) in dichloromethane (150.00 mL) at 0 °C. The mixture was stirred for 20 h. The solvent was removed under reduced pressure at 45 °C. The crude product was dissolved in saturated sodium bicarbonate solution (400.00 mL) and extracted with ethyl acetate (200.00 mL * 4). The organic phases were combined, washed with saturated brine (200.00 mL * 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to furnish Compound 25-6.

[0293] 1H NMR (400MHz, CDCl3) δ = 8.91 (s, 1H), 7.80 (s, 1H), 6.59 (s, 1H), 4.69 (br d, J=10, 6 Hz, 1H), 4.16 (dt, J=1.3, 6.2 Hz, 2H), 4.04 - 3.98 (m, 1H), 3.85 (br d, J=2, 7 Hz, 1H), 3.53 (t, J=5.9 Hz, 2H), 3.29 (s, 3H), 2.13 - 2.02 (m, 2H), 1.05 (s, 9H).

[0294] Step E: 25-7 (34.73 g, 134.40 mmol) was added to a solution of 25-6 in toluene (120.00 mL) at 15 °C. After stirring the mixture at 120 °C for 12 h, an additional 25-7 (9.98 g, 38.64 mmol) was added and the resulting mixture was stirred at 120 °C for an additional 20 h. Subsequently, trifluoroacetic acid (76.62 g, 672.00 mmol, 49.76 mL) was added to the reaction mixture and it was stirred at 40 °C for 3 h. The reaction mixture was concentrated under reduced pressure at 45 °C, the pH was adjusted to 9 to 10 with saturated sodium carbonate solution (300.00 mL), followed by extraction with ethyl acetate (200.00 mL * 2). The organic phases were combined, washed with saturated brine (200.00 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to afford Compound 25-8.

[0295] Step F: A solution of 25-8 (3.88 g, 7.37 mmol) and 2,3,5,6-tetrachloro-1,4-benzoquinone (2.18 g, 8.85 mmol) in toluene (20.00 mL) and glycol dimethyl ether (20.00 mL) was heated to 70 °C and stirred for 3 h. The mixture was evaporated to dryness under reduced pressure at 45 °C to remove the solvent, followed by addition of saturated aqueous sodium carbonate solution (300.00 mL) and extraction with ethyl acetate (100.00 mL * 3) to remove acidic impurities. The organic phases were combined, and 2.00 mol/L dilute hydrochloric acid (200.00 mL) was added and stirred for 1 h. After separating the aqueous phase, the pH value was adjusted to 10 with 2.00 mol/L sodium hydroxide solution, followed by extraction with dichloromethane (100.00 mL * 3). The organic phase was washed with water (150.00 mL * 1) and saturated brine (150.00 mL * 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to afford Compound 25-9.

[0296] Step G: 4.00 mol/L sodium hydroxide solution (494.58 μL) was added to a solution of 25-9 (60.00 mg, 116.74 μmol) in methanol (1.00 mL) at 15 °C. The mixture was stirred at 15 °C for 0.5 hour. The mixture was concentrated under reduced pressure at 45 °C. The pH of the crude product was adjusted to 6-7 with 1.00 mol/L hydrochloric acid solution and then concentrated under reduced pressure at 45 °C. The obtained crude product was purified by high-performance liquid chromatography (hydrochloric acid conditions; column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 40%-70%, 10 min) to afford Embodiment Compound 25.

[0297] ee value (enantiomeric excess): 96.654%.

[0298] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0299] 1H NMR (400MHz, CD3OD) δ = 8.63 (br s, 1H), 8.44 (s, 1H), 7.86 (br s, 1H), 6.73 (br s, 1H) , 4.62 (br s, 3H), 4.20 (br s, 2H), 3.64 (t, J=6.1 Hz, 2H), 3.38 (s, 3H), 2.17 - 2.04 (m, 2H), 1.38 - 0.85 (m, 9H). Mode 26

[0300] Compound 26-1 can be prepared by the method relating to the method of preparing Compound 25-9:

[0301] Step A: At 10 °C, copper(I) cyanide (27.88 mg, 311.30 μmol, 68.00 μL, 2.00 eq) was added to a solution of 26-1 (80 mg, 155.65 μmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL). The mixture was stirred at 140 °C for 12 h. The mixture was washed with ethyl acetate (20.00 mL) and 15% aqueous ammonia and diluted. The organic phase was concentrated under reduced pressure at 45 °C. The obtained crude product was purified by high-performance liquid chromatography (hydrochloric acid conditions; column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; elution gradient: 45%-65%, 7.8 min) to afford Embodiment Compound 26.

[0302] ee value (enantiomeric excess): 100%.

[0303] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0304] 1H NMR (400MHz, CDCl3) δ = 9.07 - 8.18 (m, 1H), 7.74 (br s, 1H), 7.06 - 6.32 (m, 2H), 5, 01 - 4.41 (m, 2H), 4.14 (br s, 3H), 3.53 (br s, 2H), 3.30 (s, 3H), 2.07 (br s, 2H), 1.30 - 0.76 (m, 9H). Mode 27

[0305] Compound 27-1 can be prepared by the method relating to the method of preparing Compound 25-9:

[0306] Step A: Suspension of 27-1 (100.00 mg, 194.56 μmol), methylboronic acid (13.98 mg, 233.47 μmol), sodium carbonate (20.62 mg, 194.56 μmol), and bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (31.78 mg, 38.91 μmol) in dioxane (1.00 mL) and water (0.20 mL) was stirred at 80 °C for 12 h under a nitrogen atmosphere. The mixture was filtered, and the filtrate was extracted with ethyl acetate (10.00 mL*3). The organic phase was washed with saturated brine (20.00 mL*1) and concentrated at 45 °C under reduced pressure. The crude product was purified by preparatory thin layer chromatography (silica gel, dichloromethane: methanol = 15:1) to furnish 27-2.

[0307] Step B: 4.00 mol/L sodium hydroxide solution (4.00 M, 443.78 μL) was added to a solution of 27-2 (55.00 mg, 110.06 μmol) in methanol (2.00 mL) at 15 °C. The mixture was stirred at 15 °C for 0.5 hour. The mixture was concentrated under reduced pressure at 45 °C. The pH of the crude product was adjusted to 6-7 with 1 mol/L hydrochloric acid solution and then concentrated under reduced pressure at 45 °C. The obtained crude product was purified by high-performance liquid chromatography (hydrochloric acid conditions; column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 40%-70%, 10 min) to afford Embodiment Compound 27.

[0308] ee value (enantiomeric excess): 96.852%.

[0309] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0310] 1H NMR (400MHz, CD3OD) δ = 8.73 (br s, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 6.63 (s, 1H), 4 .82 (br s, 1H), 4.70 - 4.54 (m, 2H), 4.15 (br s, 2H), 3.62 (t, J=6.1 Hz, 2H), 3, 38 (s, 3H), 2.23 (s, 3H), 2.10 (quin, J=6.1 Hz, 2H), 1.22 - 0.83 (m, 9H). Mode 28

[0311] Compound 28-1 can be prepared by the method relating to the method of preparing Compound 25-9:

[0312] Step A: A suspension of 28-1 (100.00 mg, 194.56 μmol), cyclopropylboronic acid (33.42 mg, 389.12 μmol), potassium phosphate (123.90 mg, 583.68 μmol), palladium acetate (218.40 μg, 9.73e-1μmol), and bis(1-adamantyl)-butyl-phosphane (697.58 μg, 1.95 μmol) in toluene (2.50 mL) and water (1.00 mL) was stirred at 90 °C for 12 h under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (20.00 mL) and filtered through diatomite, followed by addition of 20.00 mL of water. The organic phase was separated and concentrated under reduced pressure at 45 °C. The crude product was purified by preparatory thin layer chromatography (silica gel, dichloromethane: methanol = 20:1) to furnish 28-2.

[0313] Step B: 4.00 mol/L sodium hydroxide solution (4.00 M, 516.43 μL) was added to a solution of 28-2 (55.00 mg, 103.29 μmol) in methanol (2.00 mL) at 15°C. The mixture was stirred at 15°C for 0.5 hour. The pH of the mixture was adjusted to 6-7 with 1.00 mol/L hydrochloric acid solution, and the mixture was concentrated under reduced pressure at 45°C. The crude product was purified by reversed-phase column chromatography (formic acid conditions; 5% acetonitrile/water to 40% acetonitrile/water) to afford Embodiment Compound 28.

[0314] ee value (enantiomeric excess): 99.202%.

[0315] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0316] 1H NMR (400MHz, CD3OD) δ = 8.72 - 8.49 (m, 1H), 7.15 (s, 1H), 7.00 (br s, 1H), 6.89 - 6, 47 (m, 1H), 4.62 (s, 3H), 4.16 (br s, 2H), 3.65 (t, J=6.2 Hz, 2H), 3.38 (s, 3H) , 2.16 - 2.00 (m, 2H), 1.33 - 1.18 (m, 2H), 1.01 - 0.88 (m, 9H), 0.77 - 0.62 (m, 2H). Mode 29

[0317] Compound 29-1 can be prepared by the method relating to the method of preparing Compound 25-9:

[0318] Step A: A solution of 29-1 (200.00 mg, 389.12 μmol), tributyl(1-ethoxyvinyl)stannane (0.29 g, 802.99 μmol, 271.03 μL), and bis(triphenylphosphine)palladium dichloride (10.92 mg, 15.56 μmol) in dioxane (2.00 mL) was purged with nitrogen gas three times. The mixture was stirred at 90 °C for 12 h and concentrated under reduced pressure at 45 °C to afford a crude product. The crude product was purified by reversed-phase column chromatography (hydrochloric acid conditions, 5% acetonitrile/water (0.05% hydrochloric acid) = 5%–60%), and then purified by high-performance liquid chromatography (basic conditions; column: Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (0.05% ammonia)–acetonitrile]; elution gradient: 11%–38%, 12 min) to obtain Mode 29.

[0319] ee value (enantiomeric excess): 92.56%.

[0320] SFC Method (Supercritical Fluid Chromatography): Column: Chiral pak AD-3 100mm x 4.6mm ID, 3μm. Mobile phase: 5% to 40% methanol (0.05% diethylamine) in carbon dioxide. Flow rate: 3 mL/min. Wavelength: 220 nm.

[0321] 1H NMR (400MHz, CD3CD) δ = 8.59 (br s, 1H), 8.16 (s, 1H), 7.14 (br s, 1H), 6.77 (s, 1H), 5.04 - 4.95 (m, 1H), 4.76 - 4.51 (m, 2H), 4.35 - 4.22 (m, 2H), 3.63 (t, J=6.1 Hz, 2H), 3.38 (s, 3H), 2.64 (s, 3H), 2.17 (quin, J=6.1 Hz, 2H), 1.02 (s, 9H). Test modality 1: in vitro HBV test 1 Experimental objective:

[0322] The HBV DNA content in the culture supernatant of HepG2.2.15 cells was determined by real-time quantitative qPCR (real-time qPCR) assay, and the HBV surface antigen content was determined by enzyme-linked immunosorbent assay (ELISA). The inhibitory effect of the compound on HBV was evaluated by the EC50 value of the compound. 2 Experimental materials: 2.1 Cell line: HepG2.2.15 cells

[0323] HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen- 11330032; 10% serum, Invitrogen-10099141; 100 units/mL penicillin and 100 μg/mL streptomycin, Hyclone-SV30010; 1% non-essential amino acids, Invitrogen-11140050; 2mM L-glutamine, Invitrogen-25030081; 300μg/mL Geneticin, Invitrogen-10131027 2.2 Reagents: Trypsin (Invitrogen-25300062) DPBS (Corning-21031CVR) DMSO (Sigma-D2650-100 mL) High-throughput DNA purification kit yield (QIAamp 96 DNA Blood Kit, Qiagen-51162) Quick Start Quantitative Universal Probe Reagent (FastStart Universal Probe Master, Roche-04914058001) Hepatitis B Surface Antigen Quantitative Determination Kit (Autobio Diagnostics Co., Ltd., CL 0310) 2.3 Consumables and equipment: 96-well cell culture plate (Corning-3599) CO2 incubator (HERA-CELL-240) Optical sealing membrane (ABI-4311971) 96-well quantitative PCR plate (Applied Biosystems-4306737) Fluorescence quantitative PCR system (Applied Biosystems-7500 real-time PCR system) 3. Experimental procedures and methods:

[0324] 3.1 HepG2.2.15 cells (4x104 cells/well) were seeded in a 96-well plate and incubated overnight at 37°C under 5% CO2.

[0325] 3.2 On day 2, the compound was diluted to 8 concentrations with a 3-fold gradient. Compounds with different concentrations were added to the culture wells in duplicate wells. The final concentration of DMSO in the culture medium was 0.5%. 10μM ETV was used as 100% inhibition control and 0.5% DMSO was used as 0% inhibition control.

[0326] 3.3 On the 5th day, the culture medium was replaced with a fresh medium containing the compound.

[0327] 3.4 On the 8th day, the culture medium in the culture well was collected, and a part of the sample was taken for ELISA to determine the content of hepatitis B virus S antigen, a part of the sample was taken to extract DNA with a high-throughput DNA purification kit (Qiagen-51162).

[0328] 3.5 The preparation of PCR reaction solution was shown in Table 1: Table 1 The preparation of PCR reaction solution

[0329] Pre-initiator sequence: GTGTCTGCGGCGTTTTATCA

[0330] Post-initiator sequence: GACAAACGGGCAACATACCTT

[0331] Probe sequence: 5'+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC+TAMRA -3'

[0332] 3.6 15 μL of the reaction mixture was added to each well of a 96-well PCR plate, followed by the addition of 10 μL of HBV DNA sample or DNA standards to each well.

[0333] 3.7 PCR reaction conditions: heating at 95°C for 10 minutes; then denaturation at 95°C for 15 seconds, extension at 60°C for 1 minute, totaling 40 cycles.

[0334] 3.8 Determination of hepatitis B virus S antigen content by ELISA

[0335] 50 μL of sample and standard sample were collected and added to a reaction plate, respectively, followed by the addition of 50 μL of enzyme conjugate into each well, the mixture was shaken and mixed well and placed in a 37°C bath for 60 minutes. The plate was then washed with washing solution 5 times, followed by the addition of 50 μL of illuminating substrate into each well, the mixture was mixed well and allowed to react at room temperature for 10 minutes in the dark. The chemiluminescence intensity was determined by an ELISA.

[0336] 3.9 Data Analysis:

[0337] Calculation of percent inhibition: % Inh. = (1 - sample value / DMSO control value) x 100

[0338] EC50 calculation: The 50% inhibitory concentration (EC50) value of the compound on HBV was calculated by GraphPad Prism software.

[0339] 4. The experimental results were shown in Table 2 and Table 3: Table 2 Experimental results of HBV-DNA

[0340] Conclusion: The compounds of the present invention are effective in inhibiting HBV DNA in vitro. Table 3 Experimental results of HBsAg

[0341] Conclusion: The compounds of the present invention are effective in inhibiting hepatitis B surface antigen (HBsAg).

Test modality 2: Study on the binding rate of plasma proteins

[0342] The binding rate of Modality 6 proteins in plasma from humans, CD-1 mice, and SD rats was determined. 796 μL of blank plasma from humans, CD-1 mice, and SD rats was extracted, and 4 μL of test compound working solution (400 μM) or warfarin working solution (400 μM) was added to achieve a final concentration of test compound and warfarin in plasma samples of 2 μM. The samples were mixed thoroughly. The final concentration of the DMSO organic phase was 0.5%. 50 μL of the test compound and warfarin plasma sample were transferred to the sample receiving plates (three parallels), and a relative volume of the corresponding blank plasma or buffer was immediately added, ensuring that the final volume of each sample well was 100 μL, and the volume ratio of plasma to dialysis buffer was 1:1. 400 μL of stop solution was added to these samples, which was used as a T0 sample for the determination of recovery and stability. The T0 sample was stored at 2–8°C awaiting subsequent processing with other dialyzed samples. 150 μL of the test compound and warfarin plasma sample were added at the end of drug administration in each dialysis well, and 150 μL of blank dialysis buffer was added to the end of the dialysis well. The dialysis plate was then sealed with a gas-permeable membrane, placed in a humidified 5% CO2 incubator, and incubated at 37°C while shaking at approximately 100 rpm for 4 h. After dialysis was completed, 50 μL of the dialysate buffer sample and the dialysate plasma sample were pipetted into a new sample receiver plate. A relative volume of the corresponding blank plasma or buffer was added to the sample, ensuring that the final volume of each sample well was 100 μL and the volume ratio of plasma to dialysis buffer was 1:1. All samples were subjected to protein precipitation followed by LC/MS/MS analysis. The protein binding rate and recovery rate were calculated by the formulas: % Protein unbinding rate (%) = 100 * Drug concentration across dialysis membrane/Drug concentration not across dialysate; Protein binding rate (%) = 100% protein binding rate; % Recovery = 100 * (drug concentration across dialysis membrane + drug concentration not across dialysate) / Total drug concentration before dialysis. Protein binding rate and recovery rate were calculated.

[0343] Experimental results: The protein binding rate of Modality 6 in plasma from humans, CD-1 mice and SD rats was 55.7%, 50.2% and 59.4%, respectively.

[0344] Conclusion: The compound of the present invention has a moderate rate of binding to plasma proteins and a high portion of the drug binds to the protein, thus exhibiting greater plasma exposure.

Test modality 3: Study on the inhibition of cytochrome P450 isoenzyme

[0345] The inhibitory effect of the test compound on different subtypes of human cytochrome P450 isoenzyme was determined. Working solutions of the test compound, standard inhibitor (final concentration 100×) and a mixed substrate were prepared. Microsomes frozen in a -80 °C refrigerator were thawed. 2 μL of the test compound and the standard inhibitor solution were added to the corresponding wells, while 2 μL of the corresponding solvent was added to the non-inhibitor control (NIC) well and the blank control (blank) well. 20 μL of the mixed substrate solution was added to the corresponding wells except the blank well (20 μL of PB was added to the blank well). Human liver microsomes solution was prepared (it was put back in the refrigerator immediately after use and the date was marked), and 158 μL of human liver microsomes solution was added to all wells immediately. The sample plate was preincubated under a 37°C water bath, during which the coenzyme factor (NADPH) solution was prepared immediately. After 10 min, 20 μL of coenzyme factor (NADPH) solution was added to all wells. After the sample plate was uniformly shaken, it was incubated under a 37°C water bath for 10 min. 400 μL of cold acetonitrile solution (the internal standard was 200 ng/mL Tolbutamide and Labetalol) was added to terminate the reaction at the corresponding time. After the sample plate was well mixed, it was centrifuged at 4,000 rpm for 20 min to precipitate the protein. 200 μL of the supernatant was collected and added to 100 μL of water and subjected to LC/MS/MS measurement after being uniformly shaken.

[0346] The experimental results were shown in Table 4:

[0347] Conclusion: The test compounds have no inhibitory effect on CYP enzyme. Table 4. Experimental results of inhibition of cytochrome isoenzyme

Test Modality 4: Stability of Microsomal Metabolism

[0348] Experimental objective: The stability of the microsomal metabolism of the test compound (Modality 6) in three species was determined.

[0349] Experimental procedures: 1 μM of the test compound and microsomes (0.5 mg/mL) supplemented with NADPH regeneration system were incubated at 37°C. The positive controls were testosterone (substrate 3A4), propafenone (substrate 2D6) and diclofenac (substrate 2C9), respectively. The positive control and microsomes (0.5 mg/mL) supplemented with NADPH regeneration system were incubated at 37°C. Samples at different time points (0, 5, 10, 20, 30 and 60 minutes) were directly mixed with cold acetonitrile containing an internal standard to terminate the reaction. The compound and microsomes were incubated for 60 minutes without NADPH regeneration system. A parallel was set at each time point (n = 1). The samples were analyzed by LC/MS/MS. The concentration of the compound was indicated by the ratio between the peak area of the analyte and the peak area of the internal standard.

[0350] Experimental results: The remaining proportion of the compound of the present invention in rat, human and mouse liver microsomes at T = 60 min was: 113.0%, 109.1% and 102.5%, respectively.

[0351] Experimental Conclusion: The compound of the present invention has good stability in all three species: rats, humans and mice. Test Modality 5: Single-dose pharmacokinetic study in mouse/rat

[0352] Experimental purpose: Male C57BL/6 mice or SD rats were used as test animals, and the drug concentrations of the compound in plasma, liver and cerebrospinal fluid were determined after single-dose administration, and the pharmacokinetic behavior was evaluated.

[0353] Experimental procedures: Healthy adult male C57BL/6 mice or SD rats were selected and intragastrically administered. The candidate compound was mixed with an appropriate amount of 5% DMSO/95% (10% hydroxypropyl-β-cyclodextrin), vortexed, and sonicated to prepare a 0.2 mg/mL clear solution for use. After the mice were orally administered the 2 mg/kg dose, whole blood was collected for a certain period of time to prepare plasma, and liver and cerebrospinal fluid were collected. After sample pretreatment, the drug concentration was analyzed by the LC-MS/MS method. Phoenix WinNonlin software was used to calculate the pharmacokinetic parameters.

[0354] Experimental results: Table 5.

[0355] Experimental conclusion: The test compound of Modality 5 has good AUC0-last and bioavailability in mouse and rat species. Table 5 Experimental results of pharmacokinetics of the test compound in mice and rats

Test Modality 6: In vivo pharmacodynamic study of the rat model of HBV with hydrodynamic injection (HDI-HBV) via the tail vein

[0356] Experimental objective: The anti-hepatitis B virus activity of the modality compound in vivo was evaluated by the HDI mouse model.

[0357] Experimental materials: Balb/c mice, 10% HP-β-CD as vehicle, test compound, RG7834, ETV (Entecavir), plasmid pAAV2-HBV1.3mer (extracted with Qiagen EndoFree Plasmid Giga kit), core reagents including QIAamp96 DNA kit and FastStart Universal Probe Mast (ROX). The main instruments used in this experiment included centrifuge (Beckman Allegra X-15R), tissue grinder (QIAGEN-Tissue lyser II), and spectrophotometer (Thermo-NANODROP 1000).

[0358] Experimental methods:

[0359] a) The experimental design was shown in Table 6 below: Table 6: In vivo experimental design

[0360] b) On day 0, all mice were hydrodynamically injected with HBV plasmid DNA solution via the tail vein. Plasmid DNA was pretreated with sterile physiological saline prior to injection and stored at 4°C until use. Plasmid DNA solution was injected via the tail vein at a dose of 8% of the mouse's body weight within 5 seconds.

[0361] c) From day 1 to day 7, mice were administered the compound or solvent by oral gavage for 7 days. The specific administration methods were shown in Table 15-16.

[0362] d) On day 1, day 3 and day 5, blood was collected from the submandibular vein of the mice and sodium heparin was used as an anticoagulant. The blood sample was centrifuged at 7,000 x g, 4 °C to prepare plasma for HBV DNA determination.

[0363] e) On day 7, all mice were euthanized by CO2. Blood was collected from the heart to prepare plasma and liver tissue was collected. Two left liver lobes were isolated, 70 to 100 mg in size, and were frozen with liquid nitrogen immediately after collection. One of the liver lobes was used for HBV DNA detection and the other was used for backup.

[0364] f) All plasma and liver samples were stored in a refrigerator at -80 C before being sent for analysis.

[0365] Sample treatment: The HBsAg content in the serum of mice was determined by ELISA (enzyme-linked immunosorbent assay). The experimental procedure refers to the specification of the HBsAg ELISA kit.

[0366] Experimental Results: The inhibitory activity of the test compound on HBV replication in mouse HDI model was determined by measuring the HBsAg content in the plasma of mice. The HBsAg content in the plasma of mice at different dosing times was shown in Table 7 and Figure 1. Table 7 HBsAg content in the plasma of mice after dosing on different days

[0367] Conclusion:

[0368] From the HBsAg content data on day 5, the Modality 6 compound shows a better effect on reducing surface antigen than RG7834 and Entecavir at the same dose, exhibiting better efficacy.

Test Modality 7: Anti-HBV Activity in the Hepatitis B Virus (AAV-HBV) Mouse Model Mediated by Recombinant Adeno-Associated Virus Type 8 Vectors

[0369] Experimental objective:

[0370] The AAV vector-mediated HBV-infected mouse model is a rapid and efficient HBV model. Using the high hepatotropism of AAV vector, recombinant adeno-associated virus type 8 carrying 1.3 copy of HBV genome (rAAV8-1.3HBV) is injected into the tail vein of mice, which can efficiently introduce the 1.3 copy of the transported HBV genome into hepatocytes. Due to the characteristics of AAV viral vector, the vector mediated by it can express for a long time. The AAV/HBV model can continuously replicate HBV DNA and express HBsAg and HBeAg in the liver of mice.

[0371] The anti-HBV efficacy of the test compound in vivo was evaluated by determining the HBsAg content in the serum of mice after treatment with the test compound in the AAV/HBV mouse mode.

[0372] Experimental materials:

[0373] C57BL/6 mice, 10% HP-β-CD as vehicle, reference compound TDF (Tenofovir), test compound, recombinant virus rAAV8-1.3HBV, core experiment reagents including QIAamp96 DNA kit and TaqMan® Universal PCR Master Mix, Hepatitis B virus surface antigen detection kit, instruments including: centrifuge (Beckman Allegra X-15R), tissue grinder (QIAGEN-lisser II tissue grinder) and spectrophotometer (Thermo-NANODROP 1000).

[0374] Experimental procedures:

[0375] a) All mice were dosed orally on day 28 after virus injection, and the day was defined as day 0. Submaxillary blood from all mice was collected for serum collection prior to dosing. Mice were dosed once daily for four weeks. The specific dosing regimen was shown in Table 8.

[0376] b) Submaxillary blood from all mice was collected for serum collection twice a week; the blood volume collected each time was approximately 100 μL. The specific blood collection time was shown in Table 8.

[0377] c) On the 28th day, all mice were sacrificed and blood was collected from the heart for serum collection.

[0378] d) All serum samples were sent for analysis. Table 8: In vivo experimental scheme

Sample analysis:

[0379] The HBsAg content in the serum of mice was determined by ELISA (enzyme-linked immunosorbent assay). The experimental procedure refers to the specification of the HBsAg ELISA kit.

[0380] Experimental results:

[0381] a) The anti-HBV activity of the test compound in the AAV/HBV mouse model was evaluated by determining the HBsAg content in the plasma of the mice. The results were shown in Table 9 and Figure 2. Table 9 HBsAg content in the plasma of the mice after administration on different days (IU/mL)

[0382] b) Changes in body weight of rats were shown in Figure 3.

[0383] Experimental conclusion:

[0384] In this experiment, the test compound of Modality 6 was able to significantly reduce the HBsAg content in the AAV/HBV mouse model and exhibited a certain dose-effect relationship. During the course of treatment with Modality 6, the mice showed good tolerance and the changes in body weight were better than RG7834.

Test Modality 8: 14-Day Pre-Toxicological Tolerance Test in Rats

[0385] In this experiment, test compound RG7834 and Modality 6 were administered intragastrically once daily for 14 consecutive days to test potential toxicity. The experimental design was shown in Table 10: Table 10: Experimental experiment group and dosage

[0386] A total of 21 animals in this experiment were randomly divided into 7 groups. The animals were orally administered the test compounds once daily for 14 consecutive days, and toxicity was evaluated. At necropsy, animal tissue would be removed from the fixative, fixed, dehydrated, embedded, sectioned, stained, and examined microscopically. These tissues included the liver, heart, and lung of all animals, and the spleen, stomach, duodenum, jejunum, ileum, and kidney of partial animals.

Experimental results:

[0387] RG7834 Only the heart, liver and lung were examined in the medium and low dose groups, and no histopathological changes associated with the test compound were observed. The high dose group showed that the histopathological changes associated with the test compound appeared as mild myocardial degeneration in the heart, mild degeneration of central hepatic cells in the small lobules of the liver, mild decrease in white pulp lymphocytes in the spleen, and moderate acute inflammation of the duodenal mucosa.

[0388] Mode 6: Only the heart, liver and lung were examined in the medium and low dose groups, and no histopathological changes associated with the test compound were observed. The high dose group showed that the histopathological changes associated with the test compound appeared as a small or mild decrease in white pulp lymphocytes in the spleen.

[0389] Experimental conclusion: It can be seen from the experimental results that Mode 6 has higher security than RG7834.

Test Modality 9: Single-Dose Neurotoxicity Test in Rats

[0390] Experimental Objective: In this experiment, SD rats were intragastrically administered RG7834 and Modality 6 in a single dose, and potential neurobehavioral toxicities in SD rats were assessed by the functional observation combination (FOB) test.

[0391] Experimental materials and procedures: A total of 25 male SD rats were used in this experiment. At the start of dosing, the animals were approximately 7 to 8 weeks old, males weighed between 225.50 and 285.70 g, females weighed between 177.68 and 219.89 g. Animals in the composite test group were intragastrically administered 300 or 1000 mg/kg of RG7834 and 300 or 1000 mg/kg of Modality 6 dissolved in the solvent: 0.5% (w/v) hydroxypropylmethyl cellulose/0.2% (v/v) purified aqueous Tween 80 solution (pH 8.0 to 9.0). Animals in the control group were administered the solvent. All animals were administered in a volume of 10 mL/kg and subjected to the FOB test.

[0392] Experimental Results: SD rats were intragastrically administered RG7834 and Modality 6 at a single dose of 0, 300, 1000 mg/kg. At 24 hours post-administration, a test compound-associated pupil dilation appeared in male animals administered 1000 mg/kg and 300 mg/kg RG7834A. A test compound-associated pupil dilation did not appear in male animals administered 1000 mg/kg and 300 mg/kg Modality 6.

[0393] Experimental conclusion: RG7834 has a certain neurotoxic effect at high doses. In contrast, the compound of the present invention has more excellent safety.

Claims (18)

1. Compound, characterized by the fact that it presents the formula (I): or a compound selected from the group consisting of: or a pharmaceutically acceptable salt of the compound; wherein, in formula (I), Rié OH, CN, NH2, , or selected from the group consisting of , C2-5 alkenyl, C2-5 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein each of , C2-5 alkenyl, C2-5 heteroalkenyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; m is 0, 1, 2, 3, 4 or 5; R1 is not OH, CN, NH2 as long as m is 0; or, and R2is H, OH, CN, NH2, halogen or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein each of C1-3 alkyl, C1-3 heteroalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; R3 is selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl, wherein each of C1-6 alkyl and C3-6 cycloalkyl is optionally substituted with 1, 2 or 3 R; R is H, halogen, OH, CN, NH2, or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, wherein each of C1-3 alkyl, C1-3 heteroalkyl is optionally substituted with 1, 2 or 3 R'; 1. is selected from the group consisting of F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2 and CH2F; the "hetero" refers to the heteroatom or heteroatomic group; the "hetero" in C1-6 heteroalkyl, C2-5 heteroalkenyl, 3- to 6-membered heterocycloalkyl, C1-3 heteroalkyl is independently selected from the group consisting of -C(=O)N(R)-, -N(R)-, -C(=NR)-, -(R)C=N-, -S(=O)2N(R)-, -S(=O)N(R)-, N, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- and -N(R)C(=O)N(R)-; in any of the above cases, the number of the heteroatom or heteroatomic group is independently 1, 2, or 3. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that R is H, F, Cl, Br, I, OH, CN, NH2, CH3, CH3CH2, CH3O, CF3, CHF2 or CH2F. 3. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein R1 is OH, CN, NH2 or selected from the group consisting of C2-3alkenyl, C2-3heteroalkenyl, C3-6cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein each of C2-3alkenyl, C2-3heteroalkenyl, C3-6cycloalkyl and 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R. 4. The compound or pharmaceutically acceptable salt thereof according to claim 3, characterized in that R1 is OH, CN, NH2 or selected from the group consisting of in which each of is optionally replaced with 1, 2 or 3 R. 5. The compound or pharmaceutically acceptable salt thereof according to claim 4, characterized in that R1 is selected from the group consisting of OH, CN, NH2, 6. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein R2 is H, OH, CN, NH2, halogen, or selected from the group consisting of C1-3 alkyl, C1-3 heteroalkyl, and C3-6 cycloalkyl, wherein each of C1-3 alkyl, C1-3 heteroalkyl, and C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 R. 7. The compound or pharmaceutically acceptable salt thereof of claim 6, wherein R2 is H, OH, CN, NH2, F, Cl, Br, I or selected from the group consisting of CH3, in which each ofCH3, is optionally replaced with 1, 2 or 3 R. 8. The compound or pharmaceutically acceptable salt thereof according to claim 7, characterized in that R2 is selected from the group consisting of Cl, Br, CN, CH3, 9. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein R3 is selected from the group consisting of C1-4 alkyl and C3-6 cycloalkyl, wherein each of C1-4 alkyl and C3-6 cycloalkyl is optionally substituted with 1, 2 or 3 R. 10. The compound or pharmaceutically acceptable salt thereof according to claim 9, characterized in that R3 is selected from the group consisting of 11. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that m is 0, 1, 2, 3 or 4; and R1 is not OH, CN, NH2 as long as m is 0. 12. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the moiety is selected from the group consisting of 13. Compound according to any one of claims 1 to 11, characterized in that it presents formula (II), (III) or (IV), or the pharmaceutically acceptable salt thereof, wherein: 14. is H or selected from the group consisting of C1-3 alkyl and C1-3 heteroalkyl, wherein each of C1-3 alkyl and C1-3 heteroalkyl is optionally substituted with 1, 2 or 3 R; 15. is selected from the group consisting of C and N; Y is selected from the group consisting of O and C; each of L1 and L2 is independently selected from the group consisting of a single bond, -(CH2)n- and -C(=O)-; with the proviso that L1 and L2 are not both a single bond; n is 1 or 2, m, R, R2, R3 and the "hetero" in C1-3 heteroalkyl are defined in claims 1 to 11; and R4 is not H provided that m is 0. 14. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound is selected from the group consisting of: 15. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound is selected from the group consisting of: 16. Pharmaceutical composition, characterized by the fact that it comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof defined in any one of claims 1 to 15, and a pharmaceutically acceptable carrier. 17. Use of the compound or pharmaceutically acceptable salt thereof defined in any one of claims 1 to 15 or of the pharmaceutical composition defined in claim 16, characterized in that it is for manufacturing a medicament for the treatment of hepatitis B. 18. Use of the compound or pharmaceutically acceptable salt thereof defined in any one of claims 1 to 15 or of the pharmaceutical composition defined in claim 16, in combination with Tenofovir or Entecavir, characterized in that it is for manufacturing a medicament for the treatment of hepatitis B.