Hepatitis B combination therapy

Abstract

Provided herein are methods for treating hepatitis B virus and / or hepatitis D virus infection in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a first agent selected from (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, and administering to the subject an effective amount of a second agent selected from (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof, and when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Incorporation by reference of any priority application For example, any and all applications for which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application are incorporated herein by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Patent Application No. 63 / 481,763, filed January 26, 2023.

[0002] Sequence Listing Reference This application is filed with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled "ALIG087WO3 SEQ List.xml," created on January 22, 2024, and is 71 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety. [Background technology]

[0003] Hepatitis B virus (HBV) is a DNA virus and a member of the Hepadnaviridae family. HBV infects over 300 million people worldwide and is the causative agent of chronic hepatitis, cirrhosis, and liver cancer and liver diseases such as hepatocellular carcinoma. Although approved drugs exist to treat HBV by either boosting the immune system or slowing viral replication, they rarely result in a functional cure for patients with chronic hepatitis B.

[0004] Hepatitis D virus (HDV) is a DNA virus and a member of the Hepadnaviridae family. HDV can only be transmitted in the presence of HBV. The route of HDV transmission is similar to that of HBV. HDV transmission can occur either through coinfection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carriage (superinfection). Both superinfection and coinfection with HDV result in more serious complications than infection with HBV alone. These complications include a higher likelihood of liver failure and rapid progression to cirrhosis in acute infection, and an increased risk of developing liver cancer in chronic infection. When combined with hepatitis B, hepatitis D has the highest mortality rate of all hepatitis infections, at 20%. Currently, there is no cure or vaccine for hepatitis D. Summary of the Invention

[0005] The present invention provides compounds, methods, and compositions for preventing, treating, and / or curing hepatitis B virus (HBV) and / or hepatitis D virus (HDV) infection in a host, or for reducing the activity of HBV and / or HDV in a host. Provided herein are methods for treating hepatitis B virus and / or hepatitis D virus infection in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, wherein if the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof, and if the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, and the first administration of the second agent is after a delay period after the first administration of the first agent.

[0006] In some embodiments, the method is a method of treating an HBV infection. In some embodiments, the method is a method of treating an HDV infection.

[0007] In some embodiments, the first agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof and the second agent is a CAM or a pharmaceutically acceptable salt thereof, hi some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof and the second agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the CAM is a class A CAM (CAM-A). In some embodiments, the CAM is a class E CAM (CAM-E). In some embodiments, the HBsAg-reducing agent is a small interfering RNA (siRNA). In some embodiments, the HBsAg-reducing agent is an antisense oligonucleotide (ASO).

[0009] In some embodiments, the CAM is a fused pyrazole compound, a fused pyrimidone compound, or a pyrrole compound. In some embodiments, the CAM is N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-buta-3- N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1-(hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (Compound 3);[[2-[5 -[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogenphosphate (Compound 4);N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]-1,3,5-trimethyl-pyrrole-2-carboxamide (Compound 5);(S)-2-(2- (5-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (Compound 6); (R)-N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 7); BAY 41-4109 (Compound 8); GLS4 (Compound 9); NVR 3-778 (Compound 10); RG7907 (Compound 11); ABI-H0731 (Compound 12); ABI-3773 (Compound 13); ABI-4334 (Compound 14); GLP-26 (Compound 15);KL-060332 (Compound 16); AB-836 (Compound 17); VNRX-9945 (Compound 18); (R)-N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 19); JNJ-64530440 (Compound 20); EDP-514 (Compound 21); (S)-N-(3-cyano-4-fluorophenyl)-7-methyl 3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide 1,1-dioxide (Compound 22); ZM-H1505R (Compound 23); (R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2-(pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1 -carboxamide (compound 24); (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl-3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 25); 4-[5-benzyl-12-(4-bromo-3-chlorobenzoyl)-8-oxo-2,3,7,12-tetrazatricycl 2,6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (Compound 26); and (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4-[(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (Compound 27).

[0010] In some embodiments, the HBsAg reducer is an siRNA. In some embodiments, the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ). In some embodiments, the siRNA has the nucleic acid sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7. In some embodiments, the HBsAg reducer is an ASO. In some embodiments, the ASO is a compound selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche). In some embodiments, the ASO has the nucleic acid sequence set forth in SEQ ID NO:1.

[0011] In some embodiments, the first administration of the second agent occurs after the administration of the first agent has reduced the HBsAg level in the subject. In some embodiments, the first administration of the second agent occurs after the administration of the first agent has reduced the HBsAg level in the subject to a nadir. In some embodiments, the nadir comprises a period of at least one week including at least one additional dose of the first agent, wherein the at least one additional dose does not result in a statistically significant decrease in the HBsAg level.

[0012] In some embodiments, the first administration of the second agent occurs after the first agent has been continuously administered for at least one month. In some embodiments, the delay period is greater than about 50 days. In some embodiments, the delay period is greater than about two months. In some embodiments, the delay period is between about 21 days and about 168 days. In some embodiments, the delay period is between about 28 days and about 91 days. In some embodiments, the delay period is between about 8 weeks and about 18 weeks. In some embodiments, the delay period is at least about 70 days. In some embodiments, the delay period is about 50 days.

[0013] In some embodiments, the first agent is administered at least three times at regular intervals prior to administration of the second agent. In some embodiments, the second agent is Compound 1, the first agent is an siRNA having the nucleic acid sequence set forth in SEQ ID NO: 2 and SEQ ID NO: 3, and the delay period comprises at least 50 days. In some embodiments, the delay period is at least about 70 days.

[0014] In some embodiments, the delay period is determined based on measuring the subject's plasma HBsAg level. In some embodiments, the delay period is extended until the subject's HBsAg level is reduced compared to the baseline HBsAg level. In some embodiments, the delay period is extended until the subject's plasma HBsAg level reaches its nadir.

[0015] Provided herein are methods for maintaining low plasma HBsAg levels in a subject with HBV infection. In some embodiments, the methods include administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, wherein the first administration of the second agent occurs after a delay period following the first administration of the first agent. In some embodiments, when the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof. In some embodiments, when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the first agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof and the second agent is a CAM or a pharmaceutically acceptable salt thereof, hi some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof and the second agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the first agent is a small interfering RNA (siRNA) and the second agent is a class A capsid assembly modulator (CAM-A) or a class E capsid assembly modulator (CAM-E), or a pharmaceutically acceptable salt thereof. In some embodiments, the first agent is a class A capsid assembly modulator (CAM-A) or a class E capsid assembly modulator (CAM-E), or a pharmaceutically acceptable salt thereof, and the second agent is a small interfering RNA (siRNA).

[0018] Provided herein are improved methods of treating hepatitis B virus infection in a subject in whom treatment with a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, has been initiated. In some embodiments, the improved methods comprise administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, when the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof; and when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, the first administration of the second agent is after a delay period following the first administration of the first agent.

[0019] In some embodiments, the first agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof and the second agent is a CAM or a pharmaceutically acceptable salt thereof, hi some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof and the second agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the CAM is a class A CAM (CAM-A). In some embodiments, the CAM is a class E CAM (CAM-E). In some embodiments, the HBsAg reducing agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

[0021] In some embodiments, the CAM is a fused pyrazole compound or a fused pyrimidone compound. In some embodiments, the CAM is N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-buta-3- N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1-(hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (Compound 3);[[2-[5 -[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogenphosphate (Compound 4);N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]-1,3,5-trimethyl-pyrrole-2-carboxamide (Compound 5);(S)-2-(2- (5-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (Compound 6); (R)-N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 7); BAY 41-4109 (Compound 8); GLS4 (Compound 9); NVR 3-778 (Compound 10); RG7907 (Compound 11); ABI-H0731 (Compound 12); ABI-3773 (Compound 13); ABI-4334 (Compound 14); GLP-26 (Compound 15);KL-060332 (Compound 16); AB-836 (Compound 17); VNRX-9945 (Compound 18); (R)-N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 19); JNJ-64530440 (Compound 20); EDP-514 (Compound 21); (S)-N-(3-cyano-4-fluorophenyl)-7-methyl 3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide 1,1-dioxide (Compound 22); ZM-H1505R (Compound 23); (R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2-(pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1 -carboxamide (compound 24); (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl-3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 25); 4-[5-benzyl-12-(4-bromo-3-chlorobenzoyl)-8-oxo-2,3,7,12-tetrazatricycl 2,6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (Compound 26); and (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4-[(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (Compound 27).

[0022] In some embodiments, the HBsAg reducer is an siRNA. In some embodiments, the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ). In some embodiments, the siRNA has the nucleic acid sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7. In some embodiments, the HBsAg reducer is an ASO. In some embodiments, the ASO is a compound selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche). In some embodiments, the ASO has the nucleic acid sequence set forth in SEQ ID NO:1.

[0023] In some embodiments, the first administration of the second agent occurs after the first agent has been continuously administered for at least one month. In some embodiments, the delay period is greater than about 50 days. In some embodiments, the delay period is greater than about two months. In some embodiments, the delay period is between about 21 days and about 168 days. In some embodiments, the delay period is between about 28 days and about 91 days. In some embodiments, the delay period is between about 8 weeks and about 18 weeks.

[0024] In some embodiments, the first agent is administered at least three times at regular intervals prior to administration of the second agent. In some embodiments, the CAM is CAM-A, CAM-A is Compound 1, the HBsAg reducer is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:2 and SEQ ID NO:3, and the delay period comprises at least about 50 days. In some embodiments, the delay period is at least about 70 days. In some embodiments, the first agent is Compound 1 or a pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:2 and SEQ ID NO:3. In some embodiments, the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:2 and SEQ ID NO:3, and the second agent is Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the hepatitis B virus infection is a chronic hepatitis B virus infection.

[0025] In some embodiments, (a) the first agent is compound 4 or a pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7, or (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7, and the second agent is compound 4 or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the method further comprises administering an additional agent selected from the group consisting of interferon, a nucleoside analog, a nucleotide analog, a sequence-specific oligonucleotide, a nucleic acid polymer, an entry inhibitor, and a small molecule immunomodulator, hi some embodiments, the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-alpha, PEG-IFN-alpha-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, and an additional siRNA. [Brief explanation of the drawings]

[0027] [Figure 1] 1 shows the dosing schedule used in the experiments of Example 1.

[0028] [Figure 2A] 1 shows a graph depicting HBV DNA measurements over time in the experiment of Example 1.

[0029] [Figure 2B] 1 shows a graph showing HBV DNA measurements on day 189 in the experiment of Example 1.

[0030] [Figure 3A] 1 shows a graph illustrating HBsAg measurements over time in the experiment of Example 1.

[0031] [Figure 3B] 1 shows a graph showing HBsAg measurements on day 189 in the experiment of Example 1.

[0032] [Figure 4A] 1 shows a graph illustrating HBeAg measurements over time in the experiment of Example 1.

[0033] [Figure 4B] 1 shows a graph showing HBeAg measurements on day 189 in the experiment of Example 1.

[0034] [Figure 5] 1 shows the dosing schedule used in the experiments of Example 2.

[0035] [Figure 6A] 1 shows a graph depicting serum HBsAg measurements over time in the experiment of Example 2.

[0036] [Figure 6B] 1 shows a graph depicting serum HBsAg measurements over time including the add-on group in the experiment of Example 2.

[0037] [Figure 7A] 1 shows a graph depicting serum HBeAg measurements over time in the experiment of Example 2.

[0038] [Figure 7B] 1 shows a graph depicting serum HBeAg measurements over time including the add-on group in the experiment of Example 2.

[0039] [Figure 8A] 1 shows a graph depicting serum HBV DNA measurements over time in the experiment of Example 2.

[0040] [Figure 8B] 1 shows a graph depicting serum HBV DNA measurements over time including the add-on group in the experiment of Example 2.

[0041] [Figure 9] 1 shows the dosing schedule used in the experiments of Example 2.

[0042] [Figure 10A] 1 shows a graph depicting serum HBsAg measurements over time in the experiment of Example 2.

[0043] [Figure 10B] 1 shows a graph depicting serum HBsAg measurements over time including the add-on group in the experiment of Example 2.

[0044] [Figure 11A] 1 shows a graph depicting serum HBeAg measurements over time in the experiment of Example 2.

[0045] [Figure 11B] 1 shows a graph depicting serum HBeAg measurements over time including the add-on group in the experiment of Example 2.

[0046] [Figure 12A] 1 shows a graph depicting serum HBV DNA measurements over time in the experiment of Example 2.

[0047] [Figure 12B]1 shows a graph depicting serum HBV DNA measurements over time including the add-on group in the experiment of Example 2.

[0048] [Figure 13A] 1 shows a graph depicting HBV DNA measurements over time in the experiment of Example 3.

[0049] [Figure 13B] 1 shows a graph showing HBV DNA measurements on day 98 in the experiment of Example 3.

[0050] [Figure 14A] 1 shows a graph illustrating HBsAg measurements over time in the experiment of Example 3.

[0051] [Figure 14B] 1 shows a graph showing HBsAg measurements on day 98 in the experiment of Example 3.

[0052] [Figure 15A] 1 shows a graph illustrating HBeAg measurements over time in the experiment of Example 3.

[0053] [Figure 15B] 1 shows a graph showing HBeAg measurements on day 98 in the experiment of Example 3.

[0054] [Figure 16A] 1 shows a graph depicting HBV DNA measurements over time in the experiment of Example 3.

[0055] [Figure 16B] 1 shows a graph showing HBV DNA measurements on day 98 in the experiment of Example 3.

[0056] [Figure 17A] 1 shows a graph illustrating HBsAg measurements over time in the experiment of Example 3.

[0057] [Figure 17B] 1 shows a graph showing HBsAg measurements on day 98 in the experiment of Example 3.

[0058] [Figure 18A] 1 shows a graph illustrating HBeAg measurements over time in the experiment of Example 3.

[0059] [Figure 18B] 1 shows a graph showing HBeAg measurements on day 98 in the experiment of Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0060] HBV has a partially double-stranded circular DNA genome of approximately 3.2 kilobases (kb) and is classified into at least eight genotypes. The HBV replication pathway has been studied in great detail. See Tsukuda and Watashi, Hepatitis B Virus Biology and Life Cycle, Antiviral Res. 2020 Oct;182:104925. Part of replication involves the formation of a covalently closed circular (cccDNA) form. The presence of cccDNA poses a risk of viral re-emergence throughout the lifespan of the host organism. HBV carriers can transmit the disease for many years. An estimated 300 million people live with chronic hepatitis B, and more than 750,000 people worldwide are estimated to die from hepatitis B each year. In addition, immunosuppressed individuals or those receiving chemotherapy are particularly at risk for reactivation of HBV infection. Hepatitis B can be acute or chronic. Acute HBV infection can be asymptomatic or manifest as symptomatic acute hepatitis.

[0061] HBV can be transmitted by blood, semen, and / or other bodily fluids. This can occur through direct blood-to-blood contact, unprotected sex, needle sharing, but primarily from an infected mother to her newborn during the birth process. HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available medications rarely cure HBV and / or HDV infections; rather, these medications suppress viral replication.

[0062] Capsid assembly modulators (CAMs) accelerate the assembly of HBV core protein (HBc) and block the encapsidation of HBV pregenomic RNA (pgRNA) into viral particles and subsequent reverse transcription into incomplete circular DNA (rcDNA). Most CAMs also block the establishment of cccDNA, the primary reservoir of HBV. CAMs can be divided into two classes. Class A molecules, including heteroaryldihydropyrimidine (HAP) compounds, formerly known as class I molecules (CAM-1), induce the formation of large aggregates of core protein. Class E molecules, including phenylpropenamide (PPA) and sulfamoylbenzamide (SBA), formerly known as class II molecules (CAM-2), produce empty capsids lacking pgRNA.

[0063] siRNA therapy for treating HBV is described, for example, in Chen and Mahato, "siRNA Pool Targeting Different Sites of Human Hepatitis B Surface Antigen Efficiently Inhibits HBV Infection;" J Drug Target. 2008 February;16(2):140-148 and Morrissey et al., "Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs," Nature Biotechnology 23,1002-1007 (2005). RNAi is a sequence-specific post-transcriptional gene silencing mechanism that is induced by double-stranded synthetic siRNA or short hairpin RNA (shRNA) expressed intracellularly from a vector. HBV replication and expression can be inhibited by administering synthetic siRNA or endogenously expressed shRNA. See, e.g., Giladi et al., "Small interfering RNA inhibits hepatitis B virus replication in mice," Mol Ther. 2003;8(5):769-76; McCaffrey et al., "Inhibition of hepatitis B virus in mice by RNA interference," Nat Biotechnol. 2003;21(6):639-44; and Shlomai and Shaul, "Inhibition of hepatitis B virus expression and replication by RNA interference," Hepatology. 2003;37(4):764-70. HBV gene silencing can depend, for example, on the administration and sequence of siRNA, and targets of gene silencing include, for example, inhibition of viral replication and suppression of HBsAg expression.

[0064] Antisense oligonucleotide therapy for treating HBV is described, for example, in Korba and Gerin, "Antisense oligonucleotides are effective inhibitors of hepatitis B virus replication in vitro," Antiviral Res. 1995 Nov;28(3):225-42. Antisense oligonucleotides against the HBsAg gene can suppress viral production. Antisense oligonucleotides (ASOs) are effective in reducing HBsAg in animal models and CHB patients.

[0065] Therapies for treating HBV infection can be combined to obtain additional beneficial effects. For example, the administration of a first agent, such as an HBsAg-reducing agent, e.g., siRNA and / or ASO, or a CAM (Class A or Class E), can be combined with the administration of a second agent of a different type, e.g., a CAM (Class A or Class E) if the first agent is an HBsAg-reducing agent, or an HBsAg-reducing agent, e.g., siRNA and / or ASO, if the first agent is a CAM.

[0066] Surprisingly and unexpectedly, delaying the administration of a second agent for a period of time after the initial administration of a first agent (e.g., providing a CAM add-on to sequential siRNA / ASO treatment, or providing a siRNA / ASO add-on to sequential CAM treatment) provides improved results in reducing HBV infection in a subject, as opposed to initiating both treatments simultaneously, and avoids the antagonism observed when both agents are administered from the start of treatment.

[0067] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, like symbols are generally associated with like elements unless the context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein and illustrated in the drawings, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein.

[0068] It is to be understood that the present disclosure is not limited to particular embodiments described, as such may, of course, vary, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0069] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0070] All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. For purposes of this disclosure, the following terms are defined below.

[0071] definition Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0072] As used herein, the terms "treating," "treatment," "therapeutic," or "therapy" have their ordinary meanings as understood in light of the present specification and do not necessarily refer to a complete cure or elimination of a disease or condition. As used herein, the terms "treating" or "treatment" (as well understood in the art) also refer to an approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, stabilization (i.e., not worsening) of the disease state, prevention of the transmission or spread of the disease, delay or slowing of the progression of the disease, improvement or palliation of the disease state, reduction in disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. As used herein, "treating" and "treatment" also include prophylactic treatment. A method of treatment involves administering a therapeutically effective amount of an active agent to a subject. The administering step may consist of a single administration or may include a series of administrations. The composition is administered to the subject in an amount and for a duration sufficient to treat the subject. The length of the treatment period will depend on various factors, such as the severity of the condition, the age and genetic profile of the subject, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It will also be understood that the effective dosage of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Changes in dosage may occur and be obvious according to standard diagnostic analyses known in the art. In some cases, long-term administration may be required.

[0073] The term "effective amount" is used to refer to the amount of an active compound or drug that elicits the indicated biological or pharmaceutical response. For example, an effective amount of a compound may be the amount necessary to alleviate or ameliorate the symptoms of a disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human and may include alleviation of the signs or symptoms of the disease being treated. Determining an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages can be adjusted to achieve the desired effect and will depend on factors such as body weight, diet, concomitant medications, and other factors that one skilled in the medical field would recognize.

[0074] A therapeutically effective amount may also be an amount of compound sufficient to reduce HBsAg levels consistent with progression to clinical seroconversion, achieve sustained HBsAg clearance associated with a reduction in infected hepatocytes by the subject's immune system, induce a population of HBV antigen-specific activated T cells, and / or achieve sustained loss of HBsAg within 12 months. Examples of target indices include lower HBsAg below a threshold of 500 HBsAg International Units (IU), and / or higher CD8 counts. Additional examples of target indices include, but are not limited to, a serum HBV DNA level below the lower limit of quantitation (LLoQ), or below 20 IU / mL, more specifically below 15 IU / mL, more specifically below 10 IU / mL; an ALT concentration less than three times the upper limit of normal, or below 129 U / L if the subject is a male subject, or below 108 U / L if the subject is a female subject, more specifically a serum ALT concentration less than 120 U / L if the subject is a male subject, or below 105 U / L if the subject is a female subject, more specifically a serum ALT concentration less than 90 U / L if the subject is a male subject, or below 57 U / L if the subject is a female subject; HBsAg-negative serum; a serum HBsAg level of 100 IU / mL or less, more specifically below 10 IU / mL; and / or HBs seroconversion.

[0075] As used herein, the term "capsid assembly modulator" or "CAM" refers to a compound that disrupts, accelerates, inhibits, prevents, delays, reduces, or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity), or perturbs capsid stability, thereby inducing abnormal capsid morphology and function. In some embodiments, a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing abnormal capsid morphology. In another embodiment, a capsid assembly modulator interacts with a core protein (e.g., binds at an active site, binds at an allosteric site, modifies or interferes with folding, etc.), thereby interfering with capsid assembly or disassembly. In yet another embodiment, a capsid assembly modulator causes a perturbation in the structure or function of a core protein (e.g., the ability of a core protein to assemble, disassemble, bind to a substrate, fold into a proper conformation, etc.), which attenuates viral infectivity or is lethal to the virus.

[0076] As used herein, the term "fused pyrazole compound" refers to a compound having a pyrazole ring fused to another ring.

[0077] As used herein, the term "fused pyrimidone compound" refers to a compound having a pyrimidone ring fused to another ring.

[0078] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. When no substituents are specified, the specified "optionally substituted" or "substituted" group individually and independently includes deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C -means optionally substituted with one or more group(s) (one group, two groups, or three groups) selected from amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amine, and disubstituted amine.

[0079] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b " or "C a~b " refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group or a "C 1~4"Alkyl group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described by these definitions is intended.

[0080] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain, including fully saturated (no double or triple bonds) hydrocarbon groups. An alkyl group can have 1 to 20 carbon atoms. (Whenever numerical ranges such as "1 to 20" appear herein, they refer to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms; however, this definition also extends to appearances of the term "alkyl" where no numerical range is specified.) An alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms. An alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound may be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0081] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain. The length of the alkenyl can vary. For example, an alkenyl can be C 2~4Alkenyl, C 2~6 Alkenyl, or C 2~8 It can be alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl, and ethenyl. Alkenyl groups can be unsubstituted or substituted.

[0082] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. The length of an alkynyl can vary. For example, an alkynyl can be C 2~4 Alkynyl, C 2~6 Alkynyl, or C 2~8 It can be alkynyl. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.

[0083] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When consisting of two or more rings, the rings may be joined by fusion. A cycloalkyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0084] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized π-electron system throughout all rings (otherwise, the group is an "aryl," as defined herein). When composed of two or more rings, the rings may be joined by fusion. A cycloalkenyl group can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. A cycloalkenyl group can be unsubstituted or substituted.

[0085] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, aryl groups can range from C6 to C6. 14 Aryl groups, C6-C 10 The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0086] As used herein, "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole (including, for example, optionally substituted pyrazol-1-yl), benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0087] As used herein, "heterocyclyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with one to five heteroatoms, constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized π-electron system does not occur throughout all rings. The number of atoms in the rings of a heterocyclyl group may vary. For example, a heterocyclyl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to define them as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined by fusion. Additionally, any nitrogen in a heterocyclyl may be quaternized. A heterocyclyl group can be unsubstituted or substituted.Examples of such "heterocyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, tetrahydro-1,4-thi ... Examples of suitable amines include, but are not limited to, thiazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrroldione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0088] As used herein, "aryl(alkyl)" refers to an aryl group bonded as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0089] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group bonded as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs.

[0090] "(Heterocyclyl)alkyl" refers to a heterocyclyl group bonded as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of the heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0091] A "lower alkylene group" is a straight-chain -CH- linking group that forms bonds to join molecular fragments through their terminal carbon atoms. In some embodiments, a lower alkylene can contain 1, 2, 3, 4, 5, or 6 carbons. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group can be optionally substituted by replacing one or more hydrogens of the lower alkylene group with a substituent listed under the definition of "optionally substituted," and / or by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g., [ka] ) or monocyclic heterocyclyl ( [ka] etc.)

[0092] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. In some cases, alkoxy may be -OR, where R is an unsubstituted C 1~4 Alkyl. Alkoxy can be substituted or unsubstituted.

[0093] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0094] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl can be substituted or unsubstituted.

[0095] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0096] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more of the hydrogen atoms have been replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some cases, the haloalkoxy can be -OR, where R is a C substituted with 1, 2, or 3 halogens. 1~4 The haloalkoxy may be substituted or unsubstituted.

[0097] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfenyl can be substituted or unsubstituted.

[0098] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0099] A "sulfonyl" group refers to an "S(=O)R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0100] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The O-carboxy can be substituted or unsubstituted.

[0101] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0102] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0103] A "trihalomethanesulfonyl" group refers to an "X3CS(=O)2-" group where each X is a halogen.

[0104] The "trihalomethanesulfonamide" group is "X3CS(=O)2N(R A )— group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0105] As used herein, the term "amino" refers to the group --NH.sub.2.

[0106] As used herein, the term "hydroxy" refers to an --OH group.

[0107] A "cyano" group refers to a "-CN" group.

[0108] As used herein, the term "azido" refers to the group --N.sub.3.

[0109] An "isocyanato" group refers to a "-NCO" group.

[0110] A "thiocyanato" group refers to a "-SCN" group.

[0111] An "isothiocyanato" group refers to a "-NCS" group.

[0112] A "mercapto" group refers to a "-SH" group.

[0113] A "carbonyl" group refers to a -C(=O)- group.

[0114] The "S-sulfonamide" group is defined as "-S(=O)N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0115] The "N-sulfonamide" group is defined as "RS(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0116] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0117] The "N-carbamyl" group is "ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0118] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0119] The "N-thiocarbamyl group" is "ROC(=S)N(R A )-" group, where R and R Amay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0120] A "C-amide" group is a group consisting of -C(=O)N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0121] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0122] The "monosubstituted amine" group is defined as "-NHR A " group, where R A may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, the monosubstituted amine may be -NHR A wherein R A is the unsubstituted C 1~6 It may be alkyl or unsubstituted or substituted benzyl.

[0123] "Disubstituted amine" means "-NR A R B ", where R A and R B may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Disubstituted amines may be substituted or unsubstituted. In some cases, disubstituted amines may be substituted with -NR A R B wherein R A and R B are independently unsubstituted C 1~6 It may be alkyl or unsubstituted or substituted benzyl.

[0124] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0125] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0126] As used herein, the abbreviations for any protecting groups, amino acids, and other compounds are consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)), unless otherwise indicated.

[0127] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and the like, and a salt with an amino acid such as arginine and lysine.

[0128] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject has an HBV infection. In some embodiments, the subject can be a human, for example, a human with an HBV infection.

[0129] As used herein, "nadir" refers to when the measured amount of a component in a sample from a subject has decreased to a point where the amount no longer continues to decrease, even after additional administration of an agent. For example, a measured level may be said to be at its nadir if the measured level does not decrease (with statistical significance) for at least one week, at least two weeks, at least three weeks, at least four weeks, or more after at least one additional dose, at least two additional doses, at least three additional doses, at least four additional doses, or more of an agent. For example, an HBsAg level in a subject may be reduced by administration of a first agent until the HBsAg level reaches its nadir, and no statistically significant reduction in the HBsAg level is observed at least one week after administration of at least one additional dose of the first agent.

[0130] Terms and phrases used in this application, and variations thereof, particularly those in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As examples of the foregoing, the term "comprising" should be construed to mean "including without limitation," "including but not limited to," etc.; as used herein, the term "comprising" is synonymous with "comprising," "containing," or "featuring," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be construed as "having at least," the term "including" should be construed as "including, but not limited to," and the term "examples" is used to provide illustrative examples of the items under discussion, not an exhaustive or limiting list thereof. Additionally, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0131] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate for context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality.

[0132] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure compounds, enantiomerically enriched compounds, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0133] It is understood that where the compounds disclosed herein have unfilled valences, the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0134] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0135] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0136] To assist the reader of this application, the description is divided into various paragraphs or sections or directed to various embodiments of this application. These separations should not be considered as separating one paragraph, section, or embodiment from another. To the contrary, those skilled in the art will understand that the description has broad application and encompasses all combinations of the various sections, paragraphs, and sentences that may be contemplated. The discussion of any embodiment is meant to be illustrative only and is not intended to suggest that the scope of the invention, including the claims, is limited to these examples. This application contemplates the use of any of the applicable components in any combination that may be used in this application, regardless of whether a specific combination is explicitly described.

[0137] Treatment method Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as suffering from HBV and / or HDV infection an effective amount of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein (such as a first or second agent described herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HBV and / or HDV infection. Still other embodiments described herein relate to the use of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of HBV and / or HDV infection.

[0138] Some embodiments disclosed herein relate to methods of treating HBV and / or HDV infection, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HBV and / or HDV infection. Still other embodiments described herein relate to the use of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of HBV and / or HDV infection.

[0139] Some embodiments disclosed herein relate to methods of inhibiting HBV and / or HDV replication, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting HBV and / or HDV replication. Still other embodiments described herein relate to the use of a compound described herein (such as a first and / or second agent described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting HBV and / or HDV replication.

[0140] Provided herein are methods for treating hepatitis B virus and / or hepatitis D virus infection in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, when the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof; and when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the method is a method of treating an HBV infection. In some embodiments, the method is a method of treating an HDV infection.

[0142] In some embodiments, the first administration of the second agent is after a delay period following the first administration of the first agent. For example, in some embodiments, the first administration of the second agent is after a delay period following the start of administration of the first agent. For example, in some embodiments, the administration of the second agent is an add-on to the continuous treatment with the first agent.

[0143] In some embodiments, provided herein are methods for treating hepatitis B virus and / or hepatitis D virus infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg) reducer or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg reducer or a pharmaceutically acceptable salt thereof, but which is not a CAM or a pharmaceutically acceptable salt thereof when the first agent is a CAM or a pharmaceutically acceptable salt thereof, or which is not an HBsAg reducer or a pharmaceutically acceptable salt thereof when the first agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof. Thus, in some embodiments, when the first agent is an HBsAg reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof, and when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg reducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, the first administration of the second agent is after a delay period following the first administration of the first agent.

[0144] In some embodiments, the method is a method of treating an HBV infection. In some embodiments, the method is a method of treating an HDV infection.

[0145] Provided herein are methods for maintaining low plasma HBsAg levels in a subject with HBV and / or HDV infection. In some embodiments, the methods include administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, wherein if the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof; and if the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, the first administration of the second agent is after a delay period following the first administration of the first agent. In some embodiments, the method is a method of maintaining low plasma HBsAg levels in a subject with an HBV infection. In some embodiments, the method is a method of maintaining low plasma HBsAg levels in a subject with an HDV infection.

[0146] In some embodiments, the first agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof and the second agent is a CAM or a pharmaceutically acceptable salt thereof. In some embodiments, the first agent is a small interfering RNA (siRNA) and the second agent is a class A capsid assembly modulator (CAM-A) or a class E capsid assembly modulator (CAM-E) or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof, and the second agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof. In some embodiments, the first agent is a class A capsid assembly modulator (CAM-A) or a class E capsid assembly modulator (CAM-E) or a pharmaceutically acceptable salt thereof, and the second agent is a small interfering RNA (siRNA).

[0148] Further provided herein are improved methods of treating hepatitis B virus and / or hepatitis D virus infection in a subject in whom treatment with a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, is initiated. In some embodiments, the improved methods comprise administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, wherein if the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof, and if the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof. In some embodiments, the first administration of the second agent is after a delay period following the first administration of the first agent. In some embodiments, the improved method is an improved method of treating an HBV infection. In some embodiments, the improved method is an improved method of treating an HDV infection.

[0149] In some embodiments, the first agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof and the second agent is a CAM or a pharmaceutically acceptable salt thereof, hi some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof and the second agent is an HBsAg reducer or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the hepatitis B virus (HBV) infection is a chronic hepatitis B virus (HBV) infection.

[0151] Capsid assembly modulator (CAM) In some embodiments, the CAM is a class A CAM (CAM-A). In some embodiments, the CAM is a class E CAM (CAM-E).

[0152] In some embodiments, the CAM is a fused pyrazole compound. Examples of suitable fused pyrazole compounds are described in U.S. Patent Application Publication No. 2022 / 0169650. In some embodiments, the fused pyrazole compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: [ka]

[0153] During the ceremony,

[0154] X is CH, CD, CF, C(CH3) or N;

[0155] R 1 is a 3,4-substituted phenyl substituted with two moieties independently selected from the group consisting of -Cl, -Br, -CHF2, -CF3, -CH3, and -CN;

[0156] R 2 and R 3 is hydrogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, optionally substituted C 3~4 Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryl (C 1~4 alkyl), optionally substituted heteroaryl (C 1~4 alkyl), and optionally substituted heterocyclyl (C 1~4 alkyl);

[0157] R 4 and R 5 is hydrogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryl(C 1~4 alkyl), optionally substituted heteroaryl (C 1~4 alkyl), and optionally substituted heterocyclyl (C 1~4 alkyl);

[0158] R 6 and R 7 is hydrogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 independently selected from the group consisting of haloalkyl;

[0159] R 8 is -CHR 8a R 8b and;

[0160] R 8a is hydrogen or -CH3;

[0161] R 8b is the unsubstituted C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, optionally substituted monocyclic C 3~6 selected from the group consisting of cycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted monocyclic heterocyclyl; and

[0162] R 9 is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

[0163] In some embodiments, CAM is a fused pyrimidone compound. In some embodiments, the fused pyrimidone compound is of formula (II): [ka]

[0164] During the ceremony,

[0165] n is 0 or 1;

[0166] Z 1 is —C(═O)— or —NH—C(═O)—,

[0167] R 1 is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl (C 1~4 alkyl), optionally substituted heteroaryl (C 1~4 alkyl), and optionally substituted heterocyclyl (C 1~4 alkyl);

[0168] R 2 and R 3 is hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkynyl, unsubstituted C 1~4 Haloalkyl, monocyclic C 3~6 Cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl (C 1~4 alkyl), optionally substituted heteroaryl (C 1~4 alkyl), and optionally substituted heterocyclyl (C 1~4 alkyl);

[0169] R 4 and R 5 is hydrogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryl(C 1~4alkyl), optionally substituted heteroaryl (C 1~4 alkyl), and optionally substituted heterocyclyl (C 1~4 alkyl);

[0170] R 6 and R 7 is hydrogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 independently selected from the group consisting of haloalkyl;

[0171] R 8 is -NR 10A R 10B where R 10A and R 10B is not directly covalently bonded or is directly covalently bonded to a 5- to 6-membered ring, an optionally substituted heteroaryl, or an optionally substituted C 2~12 forming an alkynyl group, C 2~12 Alkynyl is an alkyl group selected from the group consisting of amino, —NH—C(═O)(unsubstituted C 1~4 alkyl), hydroxy, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 3~4 Monocyclic cycloalkyl, fluoro-substituted C 3~4 Monocyclic cycloalkyl, hydroxy-substituted C 3~4 optionally substituted with one or more substituents selected from the group consisting of monocyclic cycloalkyl, unsubstituted 4- to 6-membered monocyclic heterocyclyl, optionally substituted aryl, and optionally substituted 5- to 6-membered monocyclic heteroaryl;

[0172] R 9 is a substituted phenyl, a substituted monocyclic heteroaryl, or a substituted fused bicyclic heteroaryl, wherein the substituted phenyl, the substituted monocyclic heteroaryl, or the substituted fused bicyclic heteroaryl is selected from the group consisting of halogen, unsubstituted C 1~4 Alkyl, cyano-substituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Alkoxy, hydroxy substituted C 1~4Alkoxy, optionally substituted monocyclic C 3~6 Cycloalkyl, optionally substituted monocyclic heteroaryl, optionally substituted monocyclic heterocyclyl, amino, monosubstituted amine, disubstituted amine, and —C(═O)NHR 11 and is substituted with one or more substituents selected from the group consisting of:

[0173] R 10A is hydrogen, unsubstituted C 1~6 Monocyclic C optionally substituted with alkyl, one or two halogens 3~6 cycloalkyl, optionally substituted 5- to 6-membered monocyclic heteroaryl, optionally substituted 4- to 6-membered monocyclic heterocyclyl, or optionally substituted monocyclic C 3~6 Cycloalkyl(C 1~4 alkyl);

[0174] R 10B is an arbitrarily substituted C 2~8 Alkenyl, optionally substituted C 2~8 Alkynyl, optionally substituted aryl, optionally substituted aryl (C 1~4 alkyl), optionally substituted heteroaryl (C 1~4 alkyl), and optionally substituted heterocyclyl (C 1~4 alkyl), wherein C 2~8 Alkenyl and C 2~8 Alkynyl is substituted with amino, hydroxy, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 3~4 Monocyclic cycloalkyl, fluoro-substituted C 3~4 Monocyclic cycloalkyl, hydroxy-substituted C 3~4 optionally substituted with one or more substituents selected from the group consisting of monocyclic cycloalkyl, and unsubstituted 4- to 6-membered monocyclic heterocyclyl;

[0175] where R 10A is an optionally substituted monocyclic C 3~6 Cycloalkyl(C 1~4 alkyl), then R 10Bis the unsubstituted C 2~6 cannot be alkenyl; and

[0176] R 11 is hydrogen, unsubstituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 1~6 Alkynyl or optionally substituted C 3~6 It is a monocyclic cycloalkyl.

[0177] In some embodiments, the CAM is a pyrrole compound. Examples of suitable pyrrole compounds are described in U.S. Pat. No. 11,191,747. In some embodiments, the pyrrole compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka]

[0178] During the ceremony,

[0179] R 1 is an unsubstituted or substituted C2 alkenyl, an unsubstituted or substituted C2 alkynyl, an unsubstituted or substituted monocyclic heteroaryl, an unsubstituted or substituted bicyclic heteroaryl, or an unsubstituted or substituted monocyclic heterocyclyl, and is selected from the group consisting of C2 alkenyl, C2 alkynyl, unsubstituted C 1~4 When haloalkyl and monocyclic heteroaryl are substituted, C alkenyl, C alkynyl, and monocyclic heteroaryl are independently selected from halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 substituted with one or more substituents selected from the group consisting of cycloalkyl;

[0180] R 2 and R 3 are independently hydrogen, unsubstituted or substituted C 1~4Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1~4 Hydroxyalkyl and unsubstituted C 1~5 alkoxyalkyl; monocyclic C 3~6 When cycloalkyl and monocyclic 3-6 heterocyclyl are substituted, monocyclic C 3~6 The cycloalkyl and monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen or hydroxy; 1~4 When alkyl is substituted, C 1~4 The alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy, provided that R 2 and R 3 at least one of which is not hydrogen; or

[0181] R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3~6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, C 3~6 The cycloalkyl and 3- to 6-membered heterocyclyl are independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy;

[0182] R 4 and R 5 are independently hydrogen, halogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 2~4 is alkenyl;

[0183] R 6 is hydrogen, unsubstituted C 1~4Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 3~4 is alkenyl;

[0184] However, R 4 , R 5 and R 6 at least one of is not hydrogen; or

[0185] R 5 is hydrogen, halogen, unsubstituted C 1~4 Alkyl or unsubstituted C 2~4 alkenyl, and R 4 and R 6 together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring;

[0186] X 1 is CR A or N;

[0187] R 7a , R 7b , R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1~4 Haloalkyl, cyano, or unsubstituted C 1~4 is alkoxy;

[0188] R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH2- (α-amino acid), or -CH2-phosphate; and

[0189] R A is hydrogen, halogen, unsubstituted C 1~4 haloalkyl, or cyano.

[0190] In some embodiments, the CAM is selected from the compounds of Table A. Preferably, the CAM is a substantially pure version of a single compound; the CAM may also be a combination containing one or more compounds disclosed herein as a CAM. Table 1-1 TIFF2026503674000008.tif129155 Table 1-2 TIFF2026503674000010.tif132155 Table 1-3 TIFF2026503674000012.tif108155 Table 1-4 TIFF2026503674000014.tif132155 Table 1-5 Table 1-6

[0191] In some embodiments, the CAM is N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-buta-3- N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1-(hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (Compound 3);[[2-[5 -[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogenphosphate (Compound 4);N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]-1,3,5-trimethyl-pyrrole-2-carboxamide (Compound 5);(S)-2-(2- (5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (Compound 6); (R)-N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 7); BAY 41-4109 (compound 8); GLS4 (compound 9); NVR 3-778 (compound 10); RG7907 (compound 11); ABI-H0731 (compound 12); ABI-3773 (compound 13); ABI-4334 ( Compound 14); GLP-26 (Compound 15); KL-060332 (Compound 16); AB-836 (Compound 17); VNRX-9945 (Compound 18);(R)-N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 19); JNJ-64530440 (Compound 20); EDP-514 (Compound 21); (S)-N-(3-cyano-4-fluorophenyl)-7-methyl-3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4-b][1, 4,5]oxathiazepine-6-carboxamide 1,1-dioxide (compound 22); ZM-H1505R (compound 23); (R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2-(pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1-carboxamide (compound 24); (6R)-7-[ 4-Bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl-3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 25); 4-[5-benzyl-12-(4-bromo-3-chloro-benzoyl)-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2, 6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (compound 26); and (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4-[(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 27).

[0192] In some embodiments, the CAM is described in WO 2017 / 156255; WO 2020 / 205934; WO 2015 / 138895; WO 2019 / 241292; WO 2019 / 154343; Zlotnick et al., 2002, A Small Molecule Inhibits and Misdirects Assembly of Hepatitis B Virus Capsids, J. Virol., 76:4848-4854; WO 2018 / 172852; WO 2018 / 090862; Deres et al., 2003, Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids, Science, 299:893-896; WO 2013 / 096744; WO 2008 / 154817; WO 2016 / 161268; WO 2018 / 039531; WO 2013 / 144129; WO 2014 / 033176; WO 2020182990; WO 2020182990; WO 2022053010; WO 2020125729; WO 2022115384; U.S. Patent Application Publication No. 2020182990; and / or WO 2023205645, each of which is incorporated herein by reference in its entirety.

[0193] HBV surface antigen (HBsAg) reducer In some embodiments, the HBsAg reducing agent is a small interfering RNA (siRNA). Examples of suitable siRNAs are described in U.S. Patent Application Publication No. 2022 / 0177888.

[0194] In some embodiments, the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ).

[0195] In some embodiments, the siRNA has the nucleic acid sequence set forth in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7. These sequences are set forth in Table C below, with modifications as described in Table B. [Table 2] [Table 3]

[0196] In some embodiments, the HBsAg reducer is an siRNA selected from any of the siRNAs disclosed in WO 2016 / 077321; WO 2020 / 163747; U.S. Patent Application Publication No. 2022 / 0177888; U.S. Patent Application Publication No. 2004 / 0127446; WO 2018 / 191278; U.S. Patent No. 8,202,979; WO 2013 / 003520; U.S. Patent No. 8,349,809; or WO 2023039005, each of which is incorporated by reference herein in its entirety.

[0197] In some embodiments, the HBsAg reducing agent is an antisense oligonucleotide (ASO), hi some embodiments, the ASO is selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche).

[0198] In some embodiments, the ASO has the nucleic acid sequence set forth in SEQ ID NO: 1. This sequence is shown below in Table E, with modifications as described in Table D. [Table 4] [Table 5]

[0199] In some embodiments, the HBsAg reducer is an ASO selected from any of the ASOs disclosed in WO 97 / 003211; WO 2012 / 145697; WO 2017 / 021385; WO 2018 / 053185; U.S. Pat. No. 10,793,859; or U.S. Pat. No. 11,466,274; or WO 2023177808, each of which is incorporated by reference herein in its entirety.

[0200] In some embodiments, the HBsAg reducing agent is a nucleic acid polymer (NAP). In some embodiments, the NAP is an S antigen transport inhibiting oligonucleotide polymer (STOP). In some embodiments, the NAP is REP-2139.

[0201] In some embodiments, the HBsAg reducer is a NAP selected from any of the NAPs disclosed in WO 2004 / 024919; U.S. Patent Application Publication No. 2004 / 0162253; WO 2016 / 030863; U.S. Patent Application Publication No. 2020 / 0147124; WO 2021 / 198958, each of which is incorporated by reference herein in its entirety.

[0202] Delay Period In some embodiments, the first administration of the second agent (e.g., a CAM, siRNA, or ASO) occurs after a delay period following the first administration of the first agent (e.g., a CAM, siRNA, or ASO). In some embodiments, the first administration of the second agent occurs after a delay period following the last administration of the first agent, e.g., if the first agent is administered multiple times. In some embodiments, the first administration of the second agent occurs after a delay period following the start of administration of the first agent. For example, in some embodiments, administration of the second agent is an add-on to continuous treatment with the first agent.

[0203] In some embodiments, administration is repeated after the initial administration. For example, in some embodiments, the first agent or the second agent is administered continuously after the initial administration of the first agent or the second agent. In some embodiments, continuous administration refers to the administration of the first agent or the second agent at regular repeated intervals. For example, in some embodiments, continuous administration refers to administration once daily, twice daily, three times daily, four times daily, five or more times daily, or a range established from any of the values ​​above. In some embodiments, continuous administration refers to administration once every other day, once every three days, once every four days, once every five days, once every six days, once every week, or once every other week, or a range established from any of the values ​​above. In some embodiments, continuous administration means administration about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, about every 12 hours, about every 13 hours, about every 14 hours, about every 15 hours, about every 16 hours, about every 17 hours, about every 18 hours, about every 19 hours, about every 20 hours, about every 21 hours, about every 22 hours, about every 23 hours, about every 24 hours, etc., or a range constructed from any of the above values.

[0204] In some embodiments, the first administration of the second agent occurs after the first agent has been administered for a period of time (i.e., a delay period), such as at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months (in some embodiments, continuously).

[0205] In some embodiments, the first administration of the second agent is after a delay period following the initial (e.g., initial) administration of the first agent. In some embodiments, the delay period following the initial administration of the first agent is longer than about 1 day. In some embodiments, the delay period is longer than about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, approximately 28 days, approximately 29 days, approximately 30 days, approximately 31 days, approximately 32 days, approximately 33 days, approximately 34 days, approximately 35 days, approximately 36 days, approximately 37 days, approximately 38 days, approximately 39 days, approximately 40 days, approximately 41 days, approximately 42 days, approximately 43 days, approximately 44 days, approximately 45 days, approximately 46 days, approximately 47 days, approximately 48 days, approximately 49 days, approximately 50 days, approximately 51 days, approximately 52 days, approximately 53 days, approximately 54 days days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, about 64 days, about 65 days, about 66 days, about 67 days, about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days , about 81 days, about 82 days, about 83 days, about 84 days, about 85 days, about 86 days, about 87 days, about 88 days, about 89 days, about 90 days, about 91 days, about 92 days, about 93 days, about 94 days, about 95 days, about 96 days, about 97 days, about 98 days, about 99 days, about 100 days, or longer, or longer than a range constructed from any of the above values. In some embodiments, the delay period is at least about 70 days. In some embodiments, the delay period is at least about 50 days.

[0206] In some embodiments, the delay period is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, or a range constructed from any of the foregoing values.

[0207] In some embodiments, an effective amount of an HBsAg-reducing agent is administered to the subject, followed by an effective amount of a capsid assembly modulator, CAM, administered to the subject. In some embodiments, the first administration of the CAM is after a delay period following the first administration of the HBsAg-reducing agent. In some embodiments, the delay period is any of the delay periods provided herein.

[0208] In some embodiments, the first or second agent is administered multiple times, e.g., two, three, four, five, six, seven, etc., with an additional delay between each administration. The interval between administrations of the first or second agent can be any of the times listed above for the delay period. For example, in some embodiments, the first agent is administered at least three times at regular intervals before administration of the second agent.

[0209] In some embodiments, the first administration of the second agent occurs after the administration of the first agent has reduced HBsAg levels in the subject. For example, in some embodiments, the delay period is determined based on measuring the subject's plasma HBsAg level. In some embodiments, the delay period is extended until the subject's HBsAg level is reduced compared to the pre-treatment baseline HBsAg level. For example, in some embodiments, the delay period is extended until a ten-fold reduction in HBsAg levels is achieved compared to baseline. In other words, in such embodiments, the add-on of an HBsAg-reducing agent, such as an siRNA or ASO, begins when a ten-fold reduction in HBsAg levels is achieved compared to baseline. In some embodiments, the delay period is extended until the subject's HBsAg level compared to baseline is reduced by about one-half, about one-third, about one-quarter, about one-fifth, about one-sixth, about one-seventh, about one-eighth, about one-ninth, about one-tenth, or about one-eleventh fold. , about 12 fold, about 13 fold, about 14 fold, about 15 fold, about 16 fold, about 17 fold, about 18 fold, about 19 fold, about 20 fold, about 30 fold, about 40 fold, about 50 fold, about 60 fold, about 70 fold, about 80 fold, about 90 fold, or about 100 fold, or a range constructed from any of the foregoing values. In some embodiments, the delay period is extended to about 0.5 fold, about 12 fold, about 13 fold, about 14 fold, about 15 fold, about 16 fold, about 17 fold, about 18 fold, about 19 fold, about 20 fold, about 30 fold, about 40 fold, about 50 fold, about 60 fold, about 70 fold, about 80 fold, about 90 fold, or about 100 fold, or a range constructed from any of the foregoing values. The method is extended until there is a log reduction, about a 1 log reduction, about a 1.5 log reduction, about a 2 log reduction, about a 2.5 log reduction, about a 3 log reduction, about a 3.5 log reduction, about a 4 log reduction, or about a 5 log reduction. Thus, in some embodiments, the method may include measuring the subject's HBsAg levels periodically (e.g., daily), such as for use in comparison to a baseline.

[0210] In some embodiments, the first administration of the second agent occurs after the administration of the first agent reduces the subject's HBsAg level to a nadir. In some embodiments, the nadir comprises a period of at least one week including at least one additional dose of the first agent, wherein the at least one additional dose does not result in a statistically significant decrease in the HBsAg level. In some embodiments, the delay period is extended until the subject's plasma HBsAg level reaches a nadir, e.g., until the subject's plasma HBsAg level does not continue to decrease after at least one, at least two, at least three, at least four, at least five, or more administrations of the first agent and after at least one day, at least two days, at least three days, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or a longer period. In some embodiments, the delay period is extended until the subject's plasma HBsAg level does not further decrease after at least two additional administrations of the first agent and after at least two weeks, or at least three weeks.

[0211] In some embodiments, the delay period is determined based on measurement of another HBV marker, such as HBV RNA, HBV DNA, HBeAg, or HBcrAg. For example, in some embodiments, the delay period is extended until the subject's level of the other HBV marker is reduced compared to the pre-treatment baseline level of the other HBV marker. For example, in some embodiments, the delay period is extended until the other HBV marker level reaches a ten-fold reduction compared to baseline. In other words, in such embodiments, the add-on of an HBsAg-reducing agent, such as an siRNA or ASO, begins when the other HBV marker level reaches a ten-fold reduction compared to baseline. In some embodiments, the delay period is extended until the subject's level of the other HBV marker compared to baseline reaches about one-half, about one-third, about one-quarter, about one-fifth, about one-sixth, about one-seventh, about one-eighth, about one-ninth, about one-tenth, about one-eleventh, or about one-fifth of the reduction. In some embodiments, the delay period is extended to about 1 / 2, about 1 / 2, about 1 / 3, about 1 / 4, about 1 / 5, about 1 / 6, about 1 / 7, about 1 / 8, about 1 / 9, about 1 / 10, about 1 / 2, about 1 / 3, about 1 / 4, about 1 / 5, about 1 / 6, about 1 / 7, about 1 / 8, about 1 / 9, about 1 / 10, about 1 / 2, about 1 / 3, about 1 / 4, about 1 / 5, about 1 / 6, about 1 / 7, about 1 / 8, about 1 / 9, about 1 / 10, or a range constructed from any of the foregoing values. and / or until there is a log reduction, about a 1 log reduction, about a 1.5 log reduction, about a 2 log reduction, about a 2.5 log reduction, about a 3 log reduction, about a 3.5 log reduction, about a 4 log reduction, or about a 5 log reduction. Thus, in some embodiments, the method may include measuring the subject's levels of other HBV markers periodically (e.g., daily), such as for use in comparison to baseline.

[0212] Combination therapy In some embodiments, the first and / or second agents described herein can be used in combination with one or more additional agents for treating and / or inhibiting replicating HBV and / or HDV. Additional agents include, but are not limited to, interferon, nucleoside / nucleotide analogs, sequence-specific oligonucleotides (e.g., antisense oligonucleotides and siRNAs), nucleic acid polymers (NAPs, e.g., nucleic acid polymers that reduce HBsAg levels, examples of which include STOPS™ compounds), entry inhibitors, and / or small molecule immunomodulators. Examples of additional agents include recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. Examples of NAPs include, but are not limited to, REP 2139 and REP 2165. Exemplary siRNAs that can be used in combination with the compounds provided herein or pharmaceutically acceptable salts thereof include those described in WO 2021 / 178885, which is incorporated herein by reference for the purposes of describing the siRNA compounds provided herein, e.g., siRNAs selected from SEQ ID NOs: 1-617 and SEQ ID NO: 618.

[0213] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be administered with one or more additional agents in a single pharmaceutical composition. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be administered with one or more additional agents in two or more separate pharmaceutical compositions. Furthermore, the order of administration of a compound described herein or a pharmaceutically acceptable salt thereof with one or more additional agents may vary. [Example]

[0214] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not intended to limit the scope of the present disclosure in any way. Those skilled in the art will appreciate that many other embodiments are also within the scope of the present invention, as described above and claimed.

[0215] Example 1 The efficacy of the compounds in vivo was evaluated in adeno-associated virus-hepatitis B virus (AAV-HBV) mice. Materials and methods are shown in Tables 1-4 below. Table F lists the nucleic acid sequences used for siRNA-1, siRNA. The sequences are written using the modified nucleotide annotations found in Table B. [Table 6] [Table 7] Abbreviations: Grp = group; Vol = volume; No. An = number of animals; PO = oral gavage; SC = subcutaneous injection; BID = 12 h / twice a day at 12 h intervals.

[0216] The administration schedule is shown in Figure 1. [Table 8] [Table 9] Abbreviations: Grp = group; Vol = volume; Prep = preparation; Conc = concentration; QW = once weekly; BID = 12h / twice a day at 12-hour intervals. [Table 10]

[0217] Test article preparation: Compound 1 and siRNA-1 were provided as powders.

[0218] Vehicle (95% PEG-400, 5% Copovidone, 100 mL) preparation: 5 g of copovidone (Plasdone S-630) was weighed out. 100 g of PEG 400 was weighed out. The copovidone was added to the PEG 400 in small amounts with continuous stirring. The ingredients were mixed until a clear, colorless solution was formed. The vehicle was stored at room temperature for up to 1 week.

[0219] Preparation of Compound 1 formulation: The required amount of test compound was weighed. The test compound was added to the appropriate amount of vehicle. The mixture was heated for 10 seconds, vortexed for 10 seconds, and sonicated for 1 minute. The heating / vortexing / sonication was repeated several times until a solution was obtained. The order of these steps can be changed.

[0220] Preparation of siRNA-1 formulation: The required volume of vehicle was added to the bottle to obtain a stock solution, vortexed, and then placed at 37°C for 30 minutes, vortexing again during incubation. All powder was ensured to go into solution. The clarity of the solution was checked. A quick spin-down was performed. The solution was diluted, and the OD260 was measured after dilution. The stock solution was diluted to the target concentration according to the actual concentration calculated by the OD value. The OD value of each formulation was measured to obtain the actual concentration. The formulations were filtered using a 0.22 μM PVDF filter. The formulations were aliquoted and stored at -20°C before use.

[0221] Live phase parameters: Based on plasma viral marker levels and body weight, 20 mice were selected and randomized into 5 groups for treatment. Dead and / or moribund animals were checked daily. Obvious changes were recorded. Body weight was measured twice weekly from days 0 to 97 and once weekly from days 98 to 189.

[0222] Vehicle (Group 01) and 55 mg / kg / dose of Compound 1 (Groups 02, 04, and 05) were administered by oral gavage twice daily from days 0 to 97. 5 mg / kg / dose of siRNA-1 was injected subcutaneously on days 0, 14, 42, and 70 for Groups 03 and 04, and on days 70, 84, and 102 for Group 05.

[0223] Plasma samples of 50 μL per mouse were prepared once a week before dosing between days 0 and 189. Samples were used for quantitative detection of HBsAg, HBeAg, and HBV DNA. Mice were sacrificed on day 189.

[0224] Results: The results are shown in Figures 2A-4B. Overall, Group 02 (CAM-A alone) is superior to Group 04 (CAM-A + siRNA co-administration); Group 05 (siRNA add-on) is the best. As shown in Figures 2A-2B, rebound after the end of CAM-A treatment is only partial, while co-administration (Group 04) rebounds to near baseline. As shown in Figures 3A-3B and 4A-4B, the CAM-A effect is sustained, while rebound is observed in the siRNA (Group 03) and co-administration (Group 04) groups. As shown in Figures 4A-4B, a sustained HBeAg response was observed in the add-on group (Group 05), with no seroconversion and only a slight rebound at the last time point.

[0225] Example 2 The efficacy of the compounds in vivo was evaluated in adeno-associated virus-hepatitis B virus (AAV-HBV) mice. Materials and methods are shown in Tables 5-8 below. Table G lists the nucleic acid sequences used for siRNA-2, an siRNA. The sequences are written using the modified nucleotide annotations found in Table B. [Table 11] [Table 12] TIFF2026503674000028.tif71155 Abbreviations: Grp = group; Vol = volume; Freq = frequency; No.An = number of animals; PO = oral gavage; SC = subcutaneous injection; QOW = once every two weeks; BID = twice a day at 12-hour intervals.

[0226] The administration schedule for the experiments involving siRNA (siRNA-2, SEQ ID NOs: 4-5) + CAM-E (Compound 7) (Groups 01A, 02A, 03, 05, 06, and 07) is shown in Figure 5.

[0227] The administration schedule for the experiment involving siRNA (siRNA-2, SEQ ID NOs: 4-5) + CAM-A (Compound 1) (Groups 01B, 02B, 04, and 08-10) is shown in Figure 9. [Table 13] [Table 14] Abbreviations: Grp = group; Vol = volume; Freq = frequency; Conc = concentration; QW = once weekly; BID = 12h / twice daily at 12-hour intervals. [Table 15]

[0228] Compound 1, Compound 7, and siRNA-2 were provided as powders and formulated by Labcorp.

[0229] The vehicle (95% PEG-400, 5% copovidone, 100 mL) was prepared by the following steps: 5 g of copovidone (Plasdone S-630) was weighed out. 100 g of PEG 400 was weighed out. The copovidone was added to the PEG 400 in small amounts with continuous stirring. The ingredients were mixed until a clear, colorless solution was formed. The vehicle was stored at room temperature for up to 1 week.

[0230] The formulations of Compound 1 and Compound 7 were prepared by the following steps: The required amount of test compound was weighed out; The test compound was added to an appropriate amount of vehicle; The mixture was heated for 10 seconds, vortexed for 10 seconds, and sonicated for 1 minute; The heating / vortexing / sonication was repeated several times until a solution was obtained; The order of these steps can be changed.

[0231] The siRNA-2 formulation was prepared using the following steps: The required volume of vehicle was added to the bottle to obtain a stock solution, vortexed, and then placed at 37°C for 30 minutes, vortexing again during incubation. All powder was ensured to go into solution. The clarity of the solution was checked. If it appeared cloudy or precipitated, it was placed at 50°C for 30 minutes. A quick spin-down was performed, followed by dilution of the solution, and the OD260 was measured after dilution. The stock solution was diluted to the target concentration according to the actual concentration calculated by the OD value. The OD value of each formulation was measured to obtain the actual concentration. The formulation was filtered using a 0.22 μm PVDF filter. The formulation was aliquoted and stored at -20°C before use.

[0232] Pretreatment parameters: Animal health was monitored during the pretreatment phase of the model. Body weight was measured on day 0 before administration. Blood was collected from mice (10 μL per mouse) for serum preparation on day 0 before administration. Samples were stored at -70°C and then transferred for quantitative detection of HBsAg, HBeAg, and HBV DNA.

[0233] Live phase parameters: Animals were assigned to cages using an Excel tool based on serum HBsAg, HBeAg, and HBV DNA levels and body weight on pre-dose day 0. Values ​​for low, medium, and high HBV titers were spread to equalize group means between groups.

[0234] Cages were checked daily for dead and / or moribund animals and any obvious changes were recorded. Body weights were measured twice weekly between days 0 and 97. Additional weight measurements were applied upon justification by the principal investigator.

[0235] Vehicle was administered at 5 mL / kg / dose by oral gavage twice daily (12 hours apart) in groups 01A and 02A from days 0 to 41, and in group 1B from days 0 to 97. 5 mg / kg / dose of siRNA-2 was administered at 5 mL / kg / dose by subcutaneous injection on days 0 and 14 in groups 02A, 05, and 07, on days 0, 14, 35, and 49 in groups 02B, 08, and 10, on days 14 and 35 in group 06, and on days 70 and 84 in group 09.

[0236] Compound 7, 50 mg / kg / dose, was administered by oral gavage at 5 mL / kg / dose twice daily (12 hours apart) from days 0 to 41 in groups 03, 05, and 06, and from days 14 to 41 in group 07.

[0237] Compound 1 at 55 mg / kg / dose was administered by oral gavage twice daily (12 hours apart) from days 0 to 97 in groups 04, 08, and 09, and from days 28 to 97 in group 10.

[0238] Mice were bled weekly from days 0 to 98 to prepare 25 μL of serum per mouse. Samples were stored at −20°C and then transferred for HBsAg, HBeAg, HBV DNA, and ALT detection.

[0239] Mice in groups 01A, 02A, 03, 05, 06 and 07 were sacrificed on day 42, and mice in groups 01B, 02B, 04 and 08-10 were sacrificed on day 98.

[0240] Results: Figures 6A-6B show the antagonism of HBsAg reduction when CAM-E Compound 7 is combined with siRNA (Combo). The sequential dosing regimens (Compound 7 → Combo (D14-) and siRNA-2 → Combo (D14-)) show a slight improvement (less antagonism). Other sequential regimens are able to completely overcome the antagonism. The HBeAg readouts shown in Figures 7A-7B indicate a more limited antagonism of the combination on this parameter, likely due to the smaller magnitude of HBeAg reduction. As shown in Figures 8A and 8B, no clear antagonism or additional benefit of the sequential regimens was observed in the HBV DNA readouts.

[0241] As seen in Figures 10A-10B, the CAM-A + siRNA combination combo did not show any antagonism in reducing HBsAg measurements compared with siRNA alone (siRNA-2 (D0-14-35-49)) and even resulted in a further reduction in the first half of the study. Furthermore, the addition of CAM-A to siRNA treatment at later time points (siRNA-2 → Combo D28) also enhanced siRNA efficacy. The most favorable regimen consisted of adding siRNA to CAM-A (Compound 1 → Combo D70), which resulted in a further reduction in serum HBsAg levels starting on day 77. A similar trend was observed for HBeAg (Figures 11A-11B). Regarding HBV DNA readouts (Figures 12A-12B), there were limited differences between the regimens, likely due to the significant reduction in HBV DNA already induced by CAM-A monotherapy.

[0242] Example 3 In the following examples, initial treatment with siRNA followed by a CAM add-on was tested in vivo in mice.

[0243] The study design is described in Table 9 below. [Table 16]

[0244] QW administration of siRNA-2 continued until the end of the study (day 98). HBV DNA, HBsAg, and HBeAg were measured weekly until day 98.

[0245] Results: As shown in Figures 13A and 13B, administration of CAM-E (Compound 6) after siRNA resulted in a significant reduction in HBV DNA, even greater than in the siRNA-only group (Group 4). As shown in Figures 14A, 14B, 15A, and 15B, by day 98, the reduction in HBsAg / HBeAg was greater for the siRNA + CAM-E add-on compared to CAM-E alone, and unlike the antagonistic effect observed in the co-administration group in Example 2, no antagonistic effect was observed for the siRNA + CAM-E add-on (Group 5) compared to siRNA alone.

[0246] As shown in Figures 16A and 16B, the CAM-A (Compound 2) only group resulted in a good reduction in HBV DNA, but the siRNA + CAM-A add-on group (Group 6) resulted in an even greater reduction in HBV DNA. As shown in Figures 17A, 17B, 18A, and 18B, by day 98, the reduction in HBsAg / HBeAg was greater for the siRNA + CAM-A add-on compared to CAM-A alone, and no antagonist effect was observed for the siRNA + CAM-A add-on (Group 6) compared to siRNA alone.

[0247] Discussion: The above results suggest that sequential delayed administration may be an unexpected solution to any antagonism observed with co-administration, such as that seen in the co-administration group in Example 2.

[0248] Other Considerations This specification includes headings for reference and to aid in locating various sections. These headings are not intended to limit the scope of the concepts described therein. Such concepts may have applicability throughout the entire specification.

[0249] Each patent, patent application, publication, and document referenced herein is incorporated herein by reference in its entirety. Citation of the above patents, patent applications, publications, and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or dates of these publications or documents. Such citation does not indicate a search for the relevant disclosures. All statements as to the dates or contents of documents are based on available information and do not constitute admissions as to their accuracy or correctness.

[0250] In the foregoing description, specific details are given to provide a thorough understanding of the examples. However, it will be understood by those skilled in the art that the examples may be practiced without these specific details.

[0251] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

[0252] The methods disclosed herein include one or more steps or actions for achieving the described method. The steps and / or actions of the methods may be interchanged with one another without departing from the scope of the claims. In other words, unless a specific order of steps or actions is required for the proper operation of the described method, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the present disclosure.

[0253] In at least some of the described embodiments, one or more elements used in one embodiment may be used interchangeably in another embodiment, unless the substitution is technically not feasible. Those skilled in the art will appreciate that various other omissions, additions, and modifications can be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and variations are intended to be included within the scope of the subject matter, as defined by the appended claims.

[0254] With respect to the use of substantially any plural or singular term herein, those skilled in the art can convert from plural to singular or vice versa as appropriate to the context or application. Various singular / plural permutations may be expressly set forth herein for clarity.

[0255] The embodiments illustratively described herein may suitably be practiced in the absence of any element not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. The terms and expressions used are used as terms of description rather than limitation, and the use of such terms and expressions does not exclude equivalents of the features shown and described or portions thereof, and various modifications are possible within the scope of the claimed technology. The terms "a" or "an" can refer to one or more of the elements it modifies (e.g., "a reagent" can mean one or more reagents), unless the context clearly indicates that either one or more elements are being described. As used herein, the term "about" or "approximately" refers to a value within 10% (i.e., plus or minus 10%) of the underlying parameter, and the use of the term "about" or "approximately" at the beginning of a series of values ​​modifies each of the values ​​(i.e., "about 1, 2, and 3" refers to about 1, about 2, and about 3). For example, a weight of "about 100 grams" can include weights from 90 grams to 110 grams. Furthermore, when a list of values ​​is described herein (e.g., about 50%, 60%, 70%, 80%, 85%, or 86%), the list includes all intermediate and fractional values ​​(e.g., 54%, 85.4%). Thus, while the present technology has been specifically disclosed by exemplary embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the embodiments.

[0256] Additionally, where features or aspects of the present disclosure are described in terms of a Markush group, one of skill in the art will recognize that the present disclosure also describes any individual member or subgroup of members of the Markush group.

[0257] As will be understood by those skilled in the art, for any and all purposes, including those related to providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations thereof. Any recited range can be readily recognized as fully descriptive and permitting division of that same range into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range described herein can be readily divided into a lower third, middle third, upper third, etc. Also, as will be understood by those skilled in the art, all language such as "up to," "at least," "greater than," and "less than" refers to a range that is inclusive of the recited numbers and can be subsequently divided into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0258] All published patents, published patent applications, and other non-patent publications referenced and described herein are each incorporated herein by reference in their entirety. Moreover, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Accordingly, it should also be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present disclosure.

Claims

1. 1. A method of treating hepatitis B virus (HBV) and / or hepatitis D virus (HDV) infection in a subject in need thereof, comprising: administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to a subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof; When the first drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second drug is a CAM or a pharmaceutically acceptable salt thereof, and when the first drug is a CAM or a pharmaceutically acceptable salt thereof, the second drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof; and The method, wherein the first administration of the second agent is after a delay period following the first administration of the first agent.

2. 10. The method of claim 1, which is a method for treating HBV infection.

3. 10. The method of claim 1, which is a method for treating HDV infection.

4. The method according to any one of claims 1 to 3, wherein the first drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, and the second drug is CAM or a pharmaceutically acceptable salt thereof.

5. The method according to any one of claims 1 to 3, wherein the first drug is CAM or a pharmaceutically acceptable salt thereof, and the second drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5, wherein the CAM is a class A CAM (CAM-A) or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 5, wherein the CAM is a class E CAM (CAM-E) or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the HBsAg reducing agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

9. 7. The method of claim 6, wherein the CAM is a fused pyrazole compound, a fused pyrimidone compound, or a pyrrole compound, or a pharmaceutically acceptable salt of any of the foregoing.

10. The CAM is N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-methylbenzamide (compound 2); N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1-(hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (compound 3); [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogenphosphate (compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]-1,3,5-trimethyl-pyrrole-2-carboxamide (compound 5); (S)-2-(2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (compound 6); (R)—N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (compound 7); BAY 41-4109 (compound 8); GLS4 (compound 9); NVR 3-778 (compound 10); RG7907 (compound 11); ABI-H0731 (compound 12); ABI-3773 (compound 13); ABI-4334 (compound 14); GLP-26 (compound 15); KL-060332 (compound 16); AB-836 (compound 17); VNRX-9945 (compound 18); (R)—N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (compound 19); JNJ-64530440 (compound 20); EDP-514 (compound 21); (S)—N-(3-cyano-4-fluorophenyl)-7-methyl-3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide 1,1-dioxide (compound 22); ZM-H1505R (compound 23); (R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2-(pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1-carboxamide (compound 24); (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl-3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 25); 4-[5-benzyl-12-(4-bromo-3-chloro-benzoyl)-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (compound 26); 10. The method of any one of claims 1 to 9, wherein the compound is selected from the group consisting of (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4-[(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (Compound 27), or a pharmaceutically acceptable salt of any of the foregoing.

11. The method according to any one of claims 1 to 10, wherein the HBsAg-reducing agent is siRNA.

12. 12. The method of claim 11, wherein the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ).

13. 12. The method of claim 11, wherein the siRNA has the nucleic acid sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:

7.

14. The method according to any one of claims 1 to 10, wherein the HBsAg reducing agent is ASO.

15. 15. The method of claim 14, wherein the ASO is a compound selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche).

16. 15. The method of claim 14, wherein the ASO has the nucleic acid sequence set forth in SEQ ID NO:

1.

17. 17. The method of any one of claims 1 to 16, wherein the first administration of the second agent occurs after the administration of the first agent has reduced HBsAg levels in the subject.

18. 18. The method of claim 17, wherein the first administration of the second agent occurs after administration of the first agent has reduced HBsAg levels in the subject to a nadir.

19. 19. The method of claim 18, wherein the nadir comprises a period of at least one week including at least one additional dose of the first agent, wherein the at least one additional dose does not result in a statistically significant decrease in HBsAg levels.

20. 20. The method of any one of claims 1 to 19, wherein the first administration of the second agent occurs after the first agent has been administered continuously for at least one month.

21. 21. The method of any one of claims 1 to 20, wherein the delay period is greater than about 50 days.

22. 22. The method of any one of claims 1 to 21, wherein the delay period is greater than about 2 months.

23. 23. The method of any one of claims 1 to 22, wherein the delay period is from about 21 days to about 168 days.

24. 24. The method of any one of claims 1 to 23, wherein the delay period is from about 28 days to about 91 days.

25. 25. The method of any one of claims 1 to 24, wherein the delay period is from about 8 weeks to about 18 weeks.

26. 26. The method of any one of claims 1 to 25, wherein the delay period is about 50 days.

27. 27. The method of any one of claims 1 to 26, wherein the first agent is administered at least three times at regular intervals before the administration of the second agent.

28. 28. The method of any one of claims 1-27, wherein the second agent is Compound 1, the first agent is an siRNA having the nucleic acid sequence set forth in SEQ ID NO:2 and SEQ ID NO:3, and the delay period comprises 50 days.

29. 29. The method of any one of claims 1 to 28, wherein the delay period is determined based on measuring the subject's plasma HBsAg level.

30. 30. The method of any one of claims 1 to 29, wherein the delay period is extended until the subject's HBsAg level is reduced compared to the baseline HBsAg level.

31. 31. The method of any one of claims 1 to 30, wherein the delay period is extended until the subject's plasma HBsAg level reaches its nadir.

32. 32. The method of any one of claims 1 to 31, wherein: (a) the first agent is compound 4 or a pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7; or (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7, and the second agent is compound 4 or a pharmaceutically acceptable salt thereof.

33. 33. The method of any one of claims 1 to 32, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence-specific oligonucleotide, a nucleic acid polymer, an entry inhibitor, and a small molecule immunomodulator, or a pharmaceutically acceptable salt of any of the foregoing.

34. 34. The method of claim 33, wherein the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-alpha, PEG-IFN-alpha-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, and an additional siRNA, or a pharmaceutically acceptable salt of any of the foregoing.

35. 1. A method of maintaining low plasma HBsAg levels in a subject with HBV and / or HDV infection, comprising: administering to the subject an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg)-reducing agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to a subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof; When the first drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second drug is CAM or a pharmaceutically acceptable salt thereof, and when the first drug is CAM or a pharmaceutically acceptable salt thereof, the second drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof; The method, wherein the first administration of the second agent is after a delay period following the first administration of the first agent.

36. 36. The method of claim 35, which is a method for treating HBV infection.

37. 36. The method of claim 35, which is a method for treating HDV infection.

38. The method according to any one of claims 35 to 37, wherein the first agent is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, and the second agent is CAM or a pharmaceutically acceptable salt thereof.

39. The method according to any one of claims 35 to 37, wherein the first drug is CAM or a pharmaceutically acceptable salt thereof, and the second drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof.

40. 37. The method of claim 36, wherein the first agent is a small interfering RNA (siRNA) and the second agent is a class A capsid assembly modulator (CAM-A) or a class E capsid assembly modulator (CAM-E), or a pharmaceutically acceptable salt of any of the foregoing.

41. 40. The method of claim 39, wherein the first agent is a class A capsid assembly modulator (CAM-A) or a class E capsid assembly modulator (CAM-E), or a pharmaceutically acceptable salt of either of the foregoing, and the second agent is a small interfering RNA (siRNA).

42. 42. The method of any one of claims 35 to 41, wherein: (a) the first agent is compound 4 or a pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7; or (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7, and the second agent is compound 4 or a pharmaceutically acceptable salt thereof.

43. 43. The method of any one of claims 35-42, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence-specific oligonucleotide, a nucleic acid polymer, an entry inhibitor, and a small molecule immunomodulator, or a pharmaceutically acceptable salt of any of the foregoing.

44. 44. The method of claim 43, wherein the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-alpha, PEG-IFN-alpha-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, and an additional siRNA, or a pharmaceutically acceptable salt of any of the foregoing.

45. 1. An improved method of treating hepatitis B virus and / or hepatitis D virus infection in a subject in whom treatment with a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg) reducer or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, comprising administering to the subject an effective amount of a second agent selected from the group consisting of (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg reducer or a pharmaceutically acceptable salt thereof; When the first drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof, the second drug is CAM or a pharmaceutically acceptable salt thereof, and when the first drug is CAM or a pharmaceutically acceptable salt thereof, the second drug is an HBsAg-reducing agent or a pharmaceutically acceptable salt thereof; The improved method, wherein the first administration of said second agent is after a delay period following the first administration of said first agent.

46. 46. ​​The improved method of claim 45, wherein said improved method is an improved method for treating hepatitis B virus infection.

47. 46. ​​The improved method of claim 45, wherein said improved method is an improved method for treating hepatitis D virus infection.

48. 48. The improved method of any one of claims 45 to 47, wherein the first agent is an HBsAg reducing agent or a pharmaceutically acceptable salt thereof, and the second agent is a CAM or a pharmaceutically acceptable salt thereof.

49. 48. The improved method of any one of claims 45 to 47, wherein the first agent is a CAM or a pharmaceutically acceptable salt thereof, and the second agent is an HBsAg reducing agent or a pharmaceutically acceptable salt thereof.

50. 50. The improved method of any one of claims 45 to 49, wherein the CAM is a class A CAM (CAM-A) or a pharmaceutically acceptable salt thereof.

51. 50. The improved method of any one of claims 45 to 49, wherein the CAM is a class E CAM (CAM-E) or a pharmaceutically acceptable salt thereof.

52. 52. The improved method of any one of claims 45 to 51, wherein the HBsAg reducing agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

53. 53. The improved method of any one of claims 45-52, wherein said CAM is a fused pyrazole compound or a fused pyrimidone compound, or a pharmaceutically acceptable salt of any of the foregoing.

54. The CAM is N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-methylbenzamide (compound 2); N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1-(hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (compound 3); [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogenphosphate (compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]-1,3,5-trimethyl-pyrrole-2-carboxamide (compound 5); (S)-2-(2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (compound 6); (R)—N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (compound 7); BAY 41-4109 (compound 8); GLS4 (compound 9); NVR 3-778 (compound 10); RG7907 (compound 11); ABI-H0731 (compound 12); ABI-3773 (compound 13); ABI-4334 (compound 14); GLP-26 (compound 15); KL-060332 (compound 16); AB-836 (compound 17); VNRX-9945 (compound 18); (R)—N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxamide (compound 19); JNJ-64530440 (compound 20); EDP-514 (compound 21); (S)—N-(3-cyano-4-fluorophenyl)-7-methyl-3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide 1,1-dioxide (compound 22); ZM-H1505R (compound 23); (R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2-(pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1-carboxamide (compound 24); (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl-3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 25); 4-[5-benzyl-12-(4-bromo-3-chloro-benzoyl)-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (compound 26); 54. The improved method of any one of claims 45-53, wherein the compound is selected from the group consisting of (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4-[(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (compound 27), or a pharmaceutically acceptable salt of any of the foregoing.

55. 55. The improved method of any one of claims 45 to 54, wherein the HBsAg reducing agent is siRNA.

56. 56. The improved method of claim 55, wherein the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ).

57. 56. The improved method of claim 55, wherein the siRNA has the nucleic acid sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:

7.

58. 55. The improved method of any one of claims 45 to 54, wherein the HBsAg reducing agent is ASO.

59. 59. The improved method of claim 58, wherein the ASO is a compound selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche).

60. 59. The improved method of claim 58, wherein the ASO has the nucleic acid sequence set forth in SEQ ID NO:

1.

61. 61. The improved method of any one of claims 45-60, wherein the first administration of the second agent occurs after the first agent has been administered continuously for at least one month.

62. 62. The improved method of any one of claims 45-61, wherein said delay period is greater than about 50 days.

63. 63. The improved method of any one of claims 45 to 62, wherein said delay period is greater than about 2 months.

64. 64. The improved method of any one of claims 45 to 63, wherein said delay period is from about 21 days to about 168 days.

65. 65. The improved method of any one of claims 45 to 64, wherein said delay period is from about 28 days to about 91 days.

66. 66. The improved method of any one of claims 45 to 65, wherein said delay period is from about 8 weeks to about 18 weeks.

67. 67. The improved method of any one of claims 45 to 66, wherein the first agent is administered at least three times at regular intervals prior to administration of the second agent.

68. 68. The improved method of any one of claims 45-67, wherein the CAM is Compound 1 or a pharmaceutically acceptable salt thereof, the HBsAg reducing agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:2 and SEQ ID NO:3, and the delay period comprises 50 days.

69. 69. The improved method of any one of claims 45 to 68, wherein said hepatitis B virus infection is a chronic hepatitis B virus infection.

70. 70. The improved method of any one of claims 45-69, wherein: (a) the first agent is compound 4 or a pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7; or (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO:6 and SEQ ID NO:7, and the second agent is compound 4 or a pharmaceutically acceptable salt thereof.

71. 71. The improved method of any one of claims 45-70, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence-specific oligonucleotide, a nucleic acid polymer, an entry inhibitor, and a small molecule immunomodulator, or a pharmaceutically acceptable salt of any of the foregoing.

72. 73. The improved method of claim 72, wherein said additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-alpha, PEG-IFN-alpha-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil, and an additional siRNA, or a pharmaceutically acceptable salt of any of the foregoing.

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