Combination therapy for hepatitis b

Abstract

Provided herein are methods of 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 / or (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) 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, a second agent selected from the group consisting of (i) CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBV surface antigen (HBsAg) lowering agent or a pharmaceutically acceptable salt thereof, where when the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; and wherein the initial administration of the second agent is after a delay period after the initial administration of the first agent.

Description

[0001] Incorporate by reference any priority application

[0002] Any and all applications to which foreign or domestic priority is claimed, for example, identified in an application data sheet or request filed with this application, are hereby incorporated by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 481,763 filed on January 26, 2023.

[0003] Reference to a sequence listing

[0004] This application is submitted with a sequence listing in electronic format. The sequence listing is provided as a file titled "ALIG087WO3 SEQ List.xml" created on January 22, 2024, which is 71 KB in size. The information in the electronic sequence listing is incorporated herein by reference in its entirety. Background Art

[0005] 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 liver cancer and liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. While approved drugs exist to treat HBV by boosting the immune system or slowing viral replication, they rarely provide a functional cure for chronic hepatitis B.

[0006] Hepatitis D virus (HDV) is also a DNA virus in the Hepadnaviridae family. HDV can only reproduce in the presence of HBV. The transmission routes of HDV are similar to those of HBV. HDV can be transmitted through simultaneous infection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carrier status (superinfection). Superinfection and co-infection with HDV both lead to more severe complications than HBV infection alone. These complications include a greater likelihood of experiencing liver failure and rapid development of cirrhosis in acute infection, with an increased risk of developing liver cancer in chronic infection. In combination with hepatitis B, hepatitis D has the highest mortality rate of all hepatitis infections, at 20%. There is currently no treatment or vaccine for hepatitis D. Summary of the Invention

[0007] 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 reducing HBV and / or HDV activity 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) a HBV surface antigen (HBsAg) lowering 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) a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof, and wherein when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, and wherein the initial administration of the second agent is after a delay period after the initial administration of the first agent.

[0008] In some embodiments, the method is a method of treating HBV infection. In some embodiments, the method is a method of treating HDV infection.

[0009] In some embodiments, the first agent is an HBsAg lowering agent 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 CAM or a pharmaceutically acceptable salt thereof; and the second agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof.

[0010] 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-lowering agent is a small interfering RNA (siRNA). In some embodiments, the HBsAg-lowering agent is an antisense oligonucleotide (ASO).

[0011] In some embodiments, the CAM is a fused pyrazole compound, a fused pyrimidinone compound, or a pyrrole compound. In some embodiments, the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetraazatricyclo[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-ethynyloxetane-3-yl)amino]methyl dihydrogen phosphate (Compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetane-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-trifluoropropane-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-cyclopropyloxyphenyl)-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-tetraazatricyclo[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-hydroxypropyloxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (Compound 27). ;

[0012] In some embodiments, the HBsAg lowering agent 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 a nucleic acid sequence as shown 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 lowering agent 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 a nucleic acid sequence as shown in SEQ ID NO: 1.

[0013] In some embodiments, the initial administration of the second agent occurs after the HBsAg level in the subject has been reduced by administration of the first agent. In some embodiments, the initial administration of the second agent occurs after the HBsAg level in the subject has been reduced to a nadir by administration of the first agent. In some embodiments, the nadir includes a period of at least one week that includes at least one additional dose of the first agent, wherein the at least one additional dose does not cause a statistically significant reduction in HBsAg levels.

[0014] In some embodiments, the initial administration of the second agent occurs after the first agent has been administered continuously 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 2 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.

[0015] 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 a nucleic acid sequence as shown 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.

[0016] In some embodiments, the delay period is determined based on the measurement of the subject's plasma HBsAg level. In some embodiments, the delay period is extended until the subject's HBsAg level decreases compared to the baseline HBsAg level. In some embodiments, the delay period is extended until the subject's plasma HBsAg level reaches a nadir.

[0017] Provided herein are methods for maintaining low plasma HBsAg levels in subjects with HBV infection. 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)-lowering 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-lowering agent or a pharmaceutically acceptable salt thereof, wherein the initial administration of the second agent is after a delay period following the initial administration of the first agent. In some embodiments, when the first agent is an HBsAg-lowering 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-lowering agent or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; and wherein the second agent is a CAM or a pharmaceutically acceptable salt thereof. In some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the first agent is a short 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 short interfering RNA (siRNA).

[0020] Provided herein are improved methods for treating hepatitis B virus infection in a subject who has initiated therapy with a first agent selected from the group consisting of: (i) an HBV surface antigen (HBsAg)-lowering agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof. 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-lowering agent or a pharmaceutically acceptable salt thereof. In some embodiments, when the first agent is an HBsAg-lowering 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-lowering agent or a pharmaceutically acceptable salt thereof. In some embodiments, the initial administration of the second agent is after a delay period following the initial administration of the first agent.

[0021] In some embodiments, the first agent is an HBsAg lowering agent 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 CAM or a pharmaceutically acceptable salt thereof; and the second agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof.

[0022] 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-lowering agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

[0023] In some embodiments, the CAM is a fused pyrazole compound or a fused pyrimidinone compound. In some embodiments, the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetraazatricyclo[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-ethynyloxetane-3-yl)amino]methyl dihydrogen phosphate (Compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetane-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-trifluoropropane-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-cyclopropyloxyphenyl)-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-tetraazatricyclo[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-hydroxypropyloxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (Compound 27). ;

[0024] In some embodiments, the HBsAg lowering agent 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 a nucleic acid sequence as shown 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 lowering agent 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 a nucleic acid sequence as shown in SEQ ID NO: 1.

[0025] In some embodiments, the initial administration of the second agent occurs after the first agent has been administered continuously 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 2 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.

[0026] 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, the CAM-A is compound 1, the HBsAg lowering agent is an siRNA having the nucleic acid sequence shown 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 sequence shown in SEQ ID NO: 2 and SEQ ID NO: 3. In some embodiments, the first agent is an siRNA having the nucleic acid sequence shown 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.

[0027] 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 sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7; or (b) the first agent is an siRNA having the nucleic acid sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is compound 4 or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the method further comprises administering an additional agent selected from the group consisting of interferon, nucleoside analogs, nucleotide analogs, sequence-specific oligonucleotides, nucleic acid polymers, entry inhibitors, and small molecule immunomodulators. In some embodiments, the additional agent is selected from the group consisting of recombinant interferon α 2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clavudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil, and additional siRNA. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The dosing regimen used in the experiments of Example 1 is shown.

[0030] Figure 2A A graph showing the results of HBV DNA measurement over time in the experiment of Example 1 is shown.

[0031] Figure 2B A graph showing the results of HBV DNA measurement on day 189 in the experiment of Example 1 is shown.

[0032] Figure 3A A graph showing the results of HBsAg measurement over time in the experiment of Example 1 is shown.

[0033] Figure 3B A graph showing the results of HBsAg measurement on day 189 in the experiment of Example 1 is shown.

[0034] Figure 4A A graph showing the results of HBeAg measurements over time in the experiment of Example 1 is shown.

[0035] Figure 4B A graph showing the results of HBeAg measurement on day 189 in the experiment of Example 1 is shown.

[0036] Figure 5 The dosing regimen used in the experiments of Example 2 is shown.

[0037] Figure 6A A graph showing the results of serum HBsAg measurement over time in the experiment of Example 2 is shown.

[0038] Figure 6B Shown are graphs showing the results of serum HBsAg measurements over time in the experiment of Example 2 including additional groups.

[0039] Figure 7A A graph showing the results of serum HBeAg measurements over time in the experiment of Example 2 is shown.

[0040] Figure 7B A graph showing the results of serum HBeAg measurements over time in the experiment of Example 2 including additional groups is shown.

[0041] Figure 8A A graph showing the results of serum HBV DNA measurement over time in the experiment of Example 2 is shown.

[0042] Figure 8B Shown are graphs showing the results of serum HBV DNA measurements over time in the experiment of Example 2 including additional groups.

[0043] Figure 9 The dosing regimen used in the experiments of Example 2 is shown.

[0044] Figure 10A A graph showing the results of serum HBsAg measurement over time in the experiment of Example 2 is shown.

[0045] Figure 10B Shown are graphs showing the results of serum HBsAg measurements over time in the experiment of Example 2 including additional groups.

[0046] Figure 11AA graph showing the results of serum HBeAg measurements over time in the experiment of Example 2 is shown.

[0047] Figure 11B A graph showing the results of serum HBeAg measurements over time in the experiment of Example 2 including additional groups is shown.

[0048] Figure 12A A graph showing the results of serum HBV DNA measurement over time in the experiment of Example 2 is shown.

[0049] Figure 12B Shown are graphs showing the results of serum HBV DNA measurements over time in the experiment of Example 2 including additional groups.

[0050] Figure 13A A graph showing the results of HBV DNA measurement over time in the experiment of Example 3 is shown.

[0051] Figure 13B A graph showing the results of HBV DNA measurement on day 98 in the experiment of Example 3 is shown.

[0052] Figure 14A A graph showing the results of HBsAg measurement over time in the experiment of Example 3 is shown.

[0053] Figure 14B A graph showing the results of HBsAg measurement on day 98 in the experiment of Example 3 is shown.

[0054] Figure 15A A graph showing the results of HBeAg measurements over time in the experiment of Example 3 is shown.

[0055] Figure 15B A graph showing the results of HBeAg measurement on day 98 in the experiment of Example 3 is shown.

[0056] Figure 16A A graph showing the results of HBV DNA measurement over time in the experiment of Example 3 is shown.

[0057] Figure 16B A graph showing the results of HBV DNA measurement on day 98 in the experiment of Example 3 is shown.

[0058] Figure 17A A graph showing the results of HBsAg measurement over time in the experiment of Example 3 is shown.

[0059] Figure 17B A graph showing the results of HBsAg measurement on day 98 in the experiment of Example 3 is shown.

[0060] Figure 18AA graph showing the results of HBeAg measurements over time in the experiment of Example 3 is shown.

[0061] Figure 18B A graph showing the results of HBeAg measurement on day 98 in the experiment of Example 3 is shown. DETAILED DESCRIPTION

[0062] HBV has a partially double-stranded circular DNA genome of approximately 3.2 kilobase pairs (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 the replication cycle involves the formation of a covalently closed circular (cccDNA) form. The presence of cccDNA poses a risk of viral re-emergence throughout the host organism's lifespan. HBV carriers can transmit the disease for many years. An estimated 300 million people have chronic hepatitis B, and over 750,000 people worldwide die from hepatitis B annually. Furthermore, immunosuppressed individuals or those undergoing chemotherapy are particularly at risk for reactivation of HBV infection. Hepatitis B can be acute or chronic. Acute HBV infection can be asymptomatic or present as symptomatic acute hepatitis.

[0063] HBV can be transmitted through blood, semen, and / or other body fluids. This can occur through direct blood-to-blood contact, unprotected sexual intercourse, shared needles, and most commonly from an infected mother to her baby during childbirth. HBV surface antigen (HBsAg) is most commonly used to screen for this infection. Currently available medications rarely cure HBV and / or HDV infection. Instead, they inhibit viral replication.

[0064] Capsid assembly modulators (CAMs) block the encapsidation of HBV pregenomic RNA (pgRNA) into viral particles and its subsequent reverse transcription into relaxed circular DNA (rcDNA) by accelerating the assembly of the HBV core protein (HBc). Most CAMs also block the establishment of cccDNA, the primary reservoir of HBV. CAMs can be grouped into two classes. Class A molecules, formerly known as class I molecules (CAM-1), include heteroaryldihydropyrimidine (HAP) compounds and induce the formation of large aggregates of core protein. Class E (class E) molecules, formerly known as class II molecules (CAM-2), include phenylacrylamide (PPA) and sulfamoylbenzamide (SBA), and generate empty capsids lacking pgRNA.

[0065] siRNA therapy for the treatment of 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 Feb; 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 triggered 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 siRNA dose and sequence, and targets of gene silencing include, for example, inhibition of viral replication and inhibition of HBsAg expression.

[0066] Antisense oligonucleotide therapy for the treatment of 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 directed against the HBsAg gene can inhibit viral production. Antisense oligonucleotides (ASOs) effectively reduce HBsAg in animal models and in patients with chronic hepatitis B.

[0067] Therapies for treating HBV infection can be combined to achieve further beneficial effects. For example, administration of a first agent (such as an HBsAg-lowering agent, e.g., siRNA and / or ASO, or a CAM (Class A or E)) can be combined with administration of a second agent of a different type (e.g., a CAM (Class A or E), in which case the first agent is an HBsAg-lowering agent, or an HBsAg-lowering agent, e.g., siRNA and / or ASO, in which case the first agent is a CAM).

[0068] Surprisingly and unexpectedly, delaying the administration of the second agent for a period of time after the initial administration of the first agent (e.g., providing a CAM in addition to sequential siRNA / ASO therapy, or providing a siRNA / ASO in addition to sequential CAM therapy) provides improved results in reducing HBV infection in the subject and in avoiding the antagonism observed when the two agents are administered from the start of treatment, as opposed to initiating both therapies simultaneously.

[0069] In the following detailed description, reference is made to the accompanying drawings, which form a part thereof. In the drawings, similar symbols generally identify similar components unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not intended 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 various aspects of the present disclosure, as generally described herein and shown in the accompanying drawings, may be arranged, substituted, combined, separated, and designed in a variety of different configurations, all of which are expressly contemplated herein.

[0070] It is to be understood that this disclosure is not limited to the particular embodiments described, as such may, of course, vary. 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.

[0071] As will be apparent to those skilled in the art upon reading this disclosure, each individual embodiment described and illustrated herein has discrete components and features that may be readily separated 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 may be performed in the order of events recited or in any other order that is logically possible.

[0072] Unless otherwise indicated, all patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety.For the purposes of this disclosure, the following terms are defined as follows.

[0073] definition

[0074] Unless otherwise defined, the 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 multiple definitions for a term herein, the definitions in this section shall prevail unless otherwise stated.

[0075] As used herein, the terms "treating," "treatment," "therapeutic," or "therapy" have their ordinary meaning as understood in accordance with this specification, and do not necessarily mean a complete cure or elimination of a disease or condition. As used herein (and as is well understood in the art), the terms "treating" or "treatment" also mean a method for obtaining a beneficial or desired result (including a clinical result) in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviating or improving one or more symptoms or conditions, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread or spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing recurrence and remission of the disease, whether partial or complete, and whether detectable or undetectable. As used herein, "treating" and "treatment" also include prophylactic treatment. Methods of treatment include administering a therapeutically effective amount of an active agent to a subject. The administration step may consist of a single administration or may include a series of administrations. The composition is administered to a subject in an amount and for a duration sufficient to treat the subject. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age and genetic characteristics of the subject, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention can be increased or decreased over the course of a specific treatment or prevention regimen. Variations in dosage can be produced and become apparent by standard diagnostic assays known in the art. In some cases, long-term administration may be required.

[0076] The term "effective amount" is used to indicate the amount of an active compound or agent that elicits the indicated biological or pharmaceutical response. For example, an effective amount of a compound may be the amount required to alleviate or ameliorate the symptoms of a disease, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capabilities of those skilled in the art, given the disclosure provided herein. The effective amount of a compound disclosed herein required as a dosage will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal being considered. The dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant medications, and other factors that will be recognized by those skilled in the medical field.

[0077] A therapeutically effective amount may also be an amount of the compound sufficient to achieve: a reduction in HBsAg levels consistent with progression to clinical seroconversion; sustained HBsAg clearance associated with a reduction in infected hepatocytes by the subject's immune system; induction of a population of activated T cells specific for HBV antigens; and / or sustained loss of HBsAg within 12 months. Examples of target indices include lower HBsAg and / or higher CD8 counts below a threshold of 500 HBsAg International Units (IU). Additional examples of target indicators include, but are not limited to, a serum HBV DNA level below the lower limit of quantification (LLoQ) or below 20 IU / mL, more particularly below 15 IU / mL, more particularly below 10 IU / mL; a serum ALT concentration below 3 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 particularly below 120 U / L if the subject is a male subject, or below 105 U / L if the subject is a female subject, more particularly below 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 particularly 10 IU / mL or less; and / or HBs seroconversion.

[0078] As used herein, the term "capsid assembly modulator" or "CAM" refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (such as during maturation) or normal capsid disassembly (such as during infectivity) or perturbs capsid stability, thereby inducing abnormal capsid morphology and function. In some embodiments, the capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing abnormal capsid morphology. In another embodiment, the capsid assembly modulator interacts with the core protein (e.g., binds at the active site, binds at the allosteric site, modifies or hinders folding, etc.), thereby disrupting capsid assembly or disassembly. In another embodiment, the capsid assembly modulator causes a perturbation in the structure or function of the core protein (such as the ability of the core protein to assemble, disassemble, bind to a substrate, fold into a suitable conformation, etc.), which reduces the infectivity of the virus or is lethal to the virus.

[0079] As used herein, the term "fused pyrazole compound" refers to a compound having a pyrazole ring fused to another ring.

[0080] As used herein, the term "fused pyrimidinone compound" refers to a compound having a pyrimidinone ring fused to another ring.

[0081] Whenever a group is described as "optionally substituted", the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the one or more substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more groups (such as 1, 2 or 3 groups) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-amino substituted amines, and disubstituted amines.

[0082] As used herein, "C" wherein "a" and "b" are integers a to C b ” or “C a-b” refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, the ring of an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group may contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, “C1 to C4 alkyl” or “C 1-4 "Alkyl" groups refer to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified with respect to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described in these definitions should be assumed.

[0083] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group can have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the present definition also covers the term "alkyl" appearing without a numerical range). The alkyl group can also be a medium-sized alkyl group having 1 to 10 carbon atoms. The alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group of a compound may be designated "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.Alkyl groups can be substituted or unsubstituted.

[0084] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The length of the alkenyl group can vary. For example, the alkenyl group can be C 2-4 Alkenyl, C 2-6 Alkenyl or C 2-8 Alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl, and vinyl. Alkenyl groups can be unsubstituted or substituted.

[0085] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The length of the alkynyl group can vary. For example, the alkynyl group can be C 2-4 Alkynyl, C 2-6 Alkynyl or C2-8 Alkynyl. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.

[0086] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be joined together in a fused form. The cycloalkyl group can contain 3 to 10 atoms in the ring. It can contain 3 to 8 atoms in the ring or 3 to 6 atoms in the ring. The cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0087] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bonds do not form a completely delocalized π-electron system throughout all rings (otherwise the group would be an "aryl" as defined herein). When composed of two or more rings, the rings may be joined together in a fused form. A cycloalkenyl group may contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. A cycloalkenyl group may be unsubstituted or substituted.

[0088] 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 π electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6 to C 14 Aryl group, C6 to C 10 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.

[0089] As used herein, "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems with a completely delocalized π electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms), which are elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring 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. In addition, the term "heteroaryl" includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. 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 (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. The heteroaryl group can be substituted or unsubstituted.

[0090] As used herein, "heterocyclic group" refers to monocyclic, bicyclic and tricyclic ring systems, wherein carbon atoms together with 1 to 5 heteroatoms constitute the ring system. The heterocyclic ring may optionally contain one or more unsaturated bonds positioned in such a way that a completely delocalized π electron system does not occur throughout all rings. The number of atoms in the ring of the heterocyclic group may vary. For example, the heterocyclic 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. The heterocyclic ring may also contain one or more carbonyl or thiocarbonyl functional groups so that the definition includes oxo-systems and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, these rings may be joined together in a fused form. In addition, any nitrogen in the heterocyclic group may be quaternized. The heterocyclic group may be unsubstituted or substituted. Examples of such "heterocyclyl" groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiinane, 1,4-oxathiinene, 1,3-oxathiolane, 1,3-dithiolene, 1,3-dithiolane, 1,4-oxathiinane, 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, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidinedione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0091] As used herein, "aryl(alkyl)" refers to an aryl group attached as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0092] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group attached as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of the heteroaryl(alkyl) group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furanyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and benzo-fused analogs thereof.

[0093] "Heterocyclyl(alkyl)" refers to a heterocyclyl group attached as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl groups of the heterocyclyl(alkyl) group 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-thiazin-4-yl(methyl).

[0094] A "lower alkylene group" is a straight-chain -CH2-tethered group that forms a bond to connect molecular fragments via its terminal carbon atoms. In some embodiments, a lower alkylene group may include 1, 2, 3, 4, 5, or 6 carbons. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group may be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent listed under the definition of "substituted" and / or by replacing one or more hydrogens of the lower alkylene group with a cycloalkyl group (e.g., and ) or a monocyclic heterocyclic group (such as and ) replaces two hydrogens on the same carbon.

[0095] As used herein, "alkoxy" refers to a radical of the formula -OR, wherein R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy radicals is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. In some cases, an alkoxy radical can be -OR, wherein R is an unsubstituted C 1-4 Alkyl and alkoxy groups may be substituted or unsubstituted.

[0096] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) attached as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. Acyl groups can be substituted or unsubstituted.

[0097] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups can be substituted or unsubstituted.

[0098] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. A haloalkyl group may be substituted or unsubstituted.

[0099] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more of the hydrogen atoms are 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, a haloalkoxy group can be -OR, where R is a C substituted with 1, 2, or 3 halogens. 1-4 Alkyl. Haloalkoxy may be substituted or unsubstituted.

[0100] 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 group can be substituted or unsubstituted.

[0101] A "sulfinyl" group refers to a "-S(=O)-R" group in which R is the same as defined with respect to sulfenyl. A sulfinyl group can be substituted or unsubstituted.

[0102] A "sulfonyl" group refers to an "S(=O)2R" group in which R is the same as defined with respect to sulfenyl. A sulfonyl group can be substituted or unsubstituted.

[0103] An "O-carboxyl" group refers to an "RC(=O)O-" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0104] The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group in which R is the same as defined with respect to O-carboxy. Esters and C-carboxy groups can be substituted or unsubstituted.

[0105] A "thiocarbonyl" group refers to a "-C(=S)R" group in which R is the same as defined with respect to O-carboxyl. The thiocarbonyl group can be substituted or unsubstituted.

[0106] A "trihalomethanesulfonyl" group refers to an "X3CS(=0)2-" group wherein each X is a halogen.

[0107] A "trihalomethanesulfonylamino" group is one in which each X is a halogen and R A "X3CS(=O)" which is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) 2 N(R A )-” group.

[0108] As used herein, the term "amino" refers to a -NH2 group.

[0109] As used herein, the term "hydroxy" refers to an -OH group.

[0110] A "cyano" group refers to a "-CN" group.

[0111] As used herein, the term "azido" refers to a -N3 group.

[0112] An "isocyanate" group refers to a "-NCO" group.

[0113] A "thiocyanate" group refers to a "-SCN" group.

[0114] An "isothiocyanate" group refers to a "-NCS" group.

[0115] A "mercapto" group refers to a "-SH" group.

[0116] A "carbonyl" group refers to a -C(=O)- group.

[0117] An "S-sulfonylamino" group is one in which R A and R B"-S(=O)2N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B )" group. The S-sulfonylamino group may be substituted or unsubstituted.

[0118] An "N-sulfonylamino" group is one in which R and R A "RS(=O)2N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A )-" group. The N-sulfonylamino group may be substituted or unsubstituted.

[0119] An "O-carbamyl" group is one in which R A and R B "-OC(=O)N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B )" group. The O-carbamyl group may be substituted or unsubstituted.

[0120] An "N-carbamyl" group is one in which R and R A "ROC(=O)N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A )-" group. The N-carbamoyl group may be substituted or unsubstituted.

[0121] An "O-thiocarbamyl" group is one in which R A and R B "-OC(=S)-N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B )" group. The O-thiocarbamoyl group may be substituted or unsubstituted.

[0122] An "N-thiocarbamyl" group is one in which R and R A "ROC(=S)N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A )-" group. The N-thiocarbamoyl group may be substituted or unsubstituted.

[0123] A "C-amido" group is one in which R A and R B "-C(=O)N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B )" group. The C-acylamino group may be substituted or unsubstituted.

[0124] An "N-amido" group is one in which R and R A "RC(=O)N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A )-" group. The N-acylamino group may be substituted or unsubstituted.

[0125] "Monosubstituted amine" refers to "-NHR A ”, where R A Can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). Monosubstituted amines can be substituted or unsubstituted. In some cases, monosubstituted amines can be -NHR A , where R A Can be unsubstituted C 1-6 alkyl or unsubstituted or substituted benzyl.

[0126] "Disubstituted amine" refers to "-NR A R B ”, where R A and R B Can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The disubstituted amine can be substituted or unsubstituted. In some cases, the disubstituted amine can be -NR A R B , where R A and R B Can be independently unsubstituted C 1-6 alkyl or unsubstituted or substituted benzyl.

[0127] As used herein, the term "halogen atom" or "halogen" means any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0128] 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 halogens, which may be the same or different. For another example, "C1 to C3 alkoxyphenyl" may include one or more alkoxy groups, which may be the same or different and contain one, two, or three atoms.

[0129] As used herein, unless otherwise indicated, abbreviations for any protecting groups, amino acids, and other compounds conform to their common usage, generally accepted abbreviations, or the IUPAC-IUB Biochemical Nomenclature Commission (see, Biochem. 11:942-944 (1972)).

[0130] 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 abrogate 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 the 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 the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or a sulfonic acid (e.g., 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 ammonium salts, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), salts of organic bases (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reaction with amino acids (such as arginine and lysine).

[0131] As used herein, "subject" refers to an animal that is the subject of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, shellfish, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject suffers from HBV infection. In some embodiments, the subject can be a human, e.g., a human suffering from HBV infection.

[0132] As used herein, "nadir" refers to a point at which the measured amount of a component in a sample from a subject has decreased to a point at which the amount no longer decreases even after additional administration of an agent. For example, a measured level is said to be at a nadir when the measured level does not decrease (such as with statistical significance) for at least one week, at least two weeks, at least three weeks, at least four weeks, or longer after at least one additional dose, at least two additional doses, at least three additional doses, at least four additional doses, or more doses of an agent. For example, the HBsAg level in a subject can be reduced by administering a first agent until the HBsAg level reaches a nadir, wherein no statistically significant decrease in the HBsAg level is observed after administration of at least one additional dose of the first agent and after at least one week.

[0133] For the terms and phrases used in this application, especially in the appended claims and variations thereof, unless otherwise expressly stated, they should be understood as open-ended and not restrictive. For the aforementioned examples, the term "including" should be understood as "including but not limited to", "including but not limited to", etc.; as used herein, the term "including" is synonymous with "comprising", "containing" or "characterized by" and is inclusive or open-ended and does not exclude additional unlisted elements or method steps; the term "having" should be interpreted as "having at least"; the term "including" should be interpreted as "including but not limited to"; the term "example" is used to provide an illustrative example of the items discussed, rather than an exhaustive or limiting list thereof. In addition, the term "including" should be interpreted as synonymous with the phrase "having at least" or "including at least". When used in the context of a compound or composition, the term "including" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0134] For substantially any plural and / or singular terms used herein, those skilled in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. For clarity, the various singular / plural permutations may be expressly stated herein. The indefinite article "a" or "an" does not exclude a plurality.

[0135] It should be understood that in any compound with one or more chiral centers described herein, if absolute stereochemistry is not explicitly indicated, each center can independently be (R) configuration or (S) configuration or a mixture thereof. Therefore, the compounds provided herein can be enantiomerically pure enantiomerically enriched racemic mixtures or diastereomerically pure diastereomerically enriched stereoisomeric mixtures. In addition, it should be understood that in any compound with one or more double bonds that generate geometric isomers that can be defined as E or Z as described herein, each double bond can independently be E or Z or a mixture thereof. Similarly, it should be understood that in any compound described herein, all tautomeric forms are also intended to be included.

[0136] It is understood that where compounds disclosed herein have unfilled valencies, these are filled with hydrogen or its isotopes (eg, hydrogen-1 (protium) and hydrogen-2 (deuterium)).

[0137] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to improved metabolic stability, such as, for example, increased half-life in vivo or reduced dosage requirements. Each chemical element as represented in the compound structure may include any isotope of the element. For example, in the compound structure, it may be explicitly disclosed or understood that hydrogen atoms are present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless otherwise expressly specified in the context, the compounds mentioned herein encompass all possible isotopic forms.

[0138] Where a range of values ​​is provided, it is understood that the upper and lower limit and every intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0139] In order to help the reader of the application, the description is separated into each paragraph or part, or relates to various embodiments of the application. These separations should not be considered as the essence of a paragraph or part or embodiment being disconnected from the essence of another paragraph or part or embodiment. On the contrary, it will be understood by those skilled in the art that this description has a wide range of applications and covers all combinations of conceivable parts, paragraphs and sentences. The discussion of any embodiment is only intended to be exemplary and is not intended to imply that the scope of the present invention, including the claims, is limited to these examples. The application contemplates the use of any of the applicable components in any combination that can be used for the application, regardless of whether a specific combination is clearly described.

[0140] Treatment

[0141] Some embodiments described herein relate to a method of treating HBV and / or HDV infection, which may include administering an effective amount of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject identified as having HBV and / or HDV infection. Other embodiments described herein relate to the use of a compound as described herein (such as a first agent or a second agent as described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating HBV and / or HDV infection. Other embodiments described herein relate to the use of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, for treating HBV and / or HDV infection.

[0142] Some embodiments disclosed herein relate to a method 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 as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. Other embodiments disclosed herein relate to the use of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating HBV and / or HDV infection. Other embodiments disclosed herein relate to the use of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for treating HBV and / or HDV infection.

[0143] Some embodiments disclosed herein relate to a method of inhibiting the replication of HBV and / or HDV, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. Other embodiments disclosed herein relate to the use of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the replication of HBV and / or HDV. Other embodiments disclosed herein relate to the use of a compound as described herein (such as a first agent and / or a second agent as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for inhibiting the replication of HBV and / or HDV.

[0144] 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)-lowering 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-lowering agent or a pharmaceutically acceptable salt thereof. In some embodiments, when the first agent is an HBsAg-lowering 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-lowering agent or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the method is a method of treating HBV infection. In some embodiments, the method is a method of treating HDV infection.

[0146] In some embodiments, the initial administration of the second agent is after a delay period following the initial administration of the first agent. For example, in some embodiments, the initial administration of the second agent is after a delay period following the start of administration of the first agent. For example, in some embodiments, administration of the second agent is in addition to continuous treatment with the first agent.

[0147] In some embodiments, provided herein are methods of treating hepatitis B virus and / or hepatitis D virus infection in a subject in need thereof, the methods comprising administering to the subject an effective amount of a first agent selected from the group consisting of: (i) a HBV surface antigen (HBsAg) lowering 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) a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, but if the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is not a CAM or a pharmaceutically acceptable salt thereof, and if the first agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is not a HBsAg lowering agent or a pharmaceutically acceptable salt thereof. Thus, in some embodiments, when the first agent is an HBsAg lowering 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 lowering agent or a pharmaceutically acceptable salt thereof. In some embodiments, the initial administration of the second agent is after a delay period following the initial administration of the first agent.

[0148] In some embodiments, the method is a method of treating HBV infection. In some embodiments, the method is a method of treating HDV infection.

[0149] Provided herein are methods for maintaining low plasma HBsAg levels in subjects with HBV and / or HDV infection. 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)-lowering 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-lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg-lowering agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-lowering agent or a pharmaceutically acceptable salt thereof. In some embodiments, the initial administration of the second agent is after a delay period following the initial administration of the first agent. In some embodiments, the method is a method of maintaining low plasma HBsAg levels in a subject with HBV infection. In some embodiments, the method is a method of maintaining low plasma HBsAg levels in a subject with HDV infection.

[0150] In some embodiments, the first agent is an HBsAg lowering agent 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 short 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.

[0151] In some embodiments, the first agent is CAM or a pharmaceutically acceptable salt thereof; and the second agent is an HBsAg lowering agent 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 short interfering RNA (siRNA).

[0152] Further provided herein are improved methods for treating hepatitis B virus and / or hepatitis D virus infection in a subject who has initiated therapy with a first agent selected from the group consisting of: (i) an HBV surface antigen (HBsAg)-lowering agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof. 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-lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg-lowering agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg-lowering agent or a pharmaceutically acceptable salt thereof. In some embodiments, the initial administration of the second agent is after a delay period following the initial administration of the first agent. In some embodiments, the improved method is an improved method for treating HBV infection. In some embodiments, the improved method is an improved method for treating HDV infection.

[0153] In some embodiments, the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; and wherein the second agent is a CAM or a pharmaceutically acceptable salt thereof. In some embodiments, the first agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the hepatitis B virus (HBV) infection is chronic hepatitis B virus (HBV) infection.

[0155] Capsid assembly regulator (CAM)

[0156] In some embodiments, the CAM is a Class A CAM (CAM-A).In some embodiments, the CAM is a Class E CAM (CAM-E).

[0157] In some embodiments, the CAM is a fused pyrazole compound. Examples of suitable fused pyrazole compounds are described in U.S. Application Publication No. 2022 / 0169650 A1. In some embodiments, the fused pyrazole compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0158] in: X is CH, CD, CF, C(CH3) or N; R 1is 3,4-substituted phenyl substituted with two moieties independently selected from the group consisting of: -Cl, -Br, -CHF2, -CF3, -CH3, and -CN; R 2 and R 3 independently selected from the group consisting of 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 heterocyclic group (C 1-4 alkyl); R 4 and R 5 independently selected from the group consisting of 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 heterocyclic group (C 1-4 alkyl); R 6 and R 7 independently selected from the group consisting of hydrogen, unsubstituted C 1-4 Alkyl and unsubstituted C 1-4 alkyl halide; R 8 -CHR 8a R 8b ; R 8a is hydrogen or -CH3; R 8b Selected from the group consisting of: unsubstituted C 1-4 Alkyl, unsubstituted C 2-4 Alkenyl, unsubstituted C 2-4 Alkynyl, optionally substituted monocyclic C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted monocyclic heterocyclyl; and R 9 is a substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclic group.

[0159] In some embodiments, the CAM is a fused pyrimidinone compound. In some embodiments, the fused pyrimidinone compound has formula (II) or a pharmaceutically acceptable salt thereof;

[0160] in: n is 0 or 1; Z 1 is -C(=O)- or -NH-C(=O)-; R 1 is selected from the group consisting of 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 heterocyclic group (C 1-4 alkyl); R 2 and R 3 are independently selected from the group consisting of hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Haloalkyl, optionally substituted monocyclic C 3-6 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 heterocyclic group (C 1-4 alkyl); R 4 and R 5 independently selected from the group consisting of 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 heterocyclic group (C 1-4 alkyl); R 6 and R 7 independently selected from the group consisting of hydrogen, unsubstituted C 1-4 Alkyl and unsubstituted C 1-4 alkyl halide; R 8 -NR 10A R 10B , where R10A and R 10B Not directly covalently linked or directly covalently linked to form a 5-6 membered ring, an optionally substituted heteroaryl or an optionally substituted C 2-12 Alkynyl, wherein the C 2-12 Alkynyl is optionally substituted with one or more substituents selected from the group consisting of amino, -NH-C(=O) (unsubstituted C 1-4 alkyl), hydroxyl, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 3-4 Monocyclic cycloalkyl, fluorine-substituted C 3-4 Monocyclic cycloalkyl, hydroxy substituted C 3-4 monocyclic cycloalkyl, unsubstituted 4-6 membered monocyclic heterocyclyl, optionally substituted aryl and optionally substituted 5-6 membered monocyclic heteroaryl; R 9 is substituted phenyl, substituted monocyclic heteroaryl or substituted fused-bicyclic heteroaryl, wherein the substituted phenyl, substituted monocyclic heteroaryl or substituted fused-bicyclic heteroaryl is substituted by one or more substituents 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 1-4 Alkoxy, 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 ; R 10A is hydrogen, unsubstituted C 1-6 Alkyl, monocyclic C optionally substituted by one or two halogens 3-6 cycloalkyl, optionally substituted 5-6 membered monocyclic heteroaryl, optionally substituted 4-6 membered monocyclic heterocyclyl or optionally substituted monocyclic C 3-6 Cycloalkyl (C 1-4 alkyl); R 10B Selected from the group consisting of: optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted aryl, optionally substituted aryl (C 1-4 alkyl), optionally substituted heteroaryl ( 1-4 alkyl) and optionally substituted heterocyclic group (C 1-4 alkyl), wherein the C 2-8 Alkenyl and C 2-8The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 3-4 Monocyclic cycloalkyl, fluorine-substituted C 3-4 Monocyclic cycloalkyl, hydroxy substituted C 3-4 Monocyclic cycloalkyl and unsubstituted 4-6 membered monocyclic heterocyclyl; When R 10A is an optionally substituted monocyclic C 3-6 Cycloalkyl (C 1-4 alkyl), then R 10B Cannot be unsubstituted C 2-6 alkenyl; and 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 Monocyclic cycloalkyl.

[0161] In some embodiments, the CAM is an azole compound. Examples of suitable azole compounds are described in U.S. Patent No. 11,191,747. In some embodiments, the azole compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0162] in: 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 heterocyclic group, wherein when the C2 alkenyl, C2 alkynyl, unsubstituted C 1-4 When the haloalkyl and monocyclic heteroaryl groups are substituted, the C2 alkenyl, C2 alkynyl and monocyclic heteroaryl groups are independently substituted with one or more substituents selected from the group consisting of 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 Cycloalkyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted or substituted monocyclic C 3-6Cycloalkyl, unsubstituted or substituted monocyclic 3-6 membered heterocyclic group, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 Alkoxyalkyl, wherein when the monocyclic C 3-6 When the cycloalkyl group and the monocyclic 3-6 heterocyclic group are substituted, the monocyclic C 3-6 The cycloalkyl and monocyclic 3-6 heterocyclic groups are independently substituted by one or more substituents selected from the group consisting of halogen or hydroxy, and wherein when C 1-4 When the alkyl group is substituted, the C 1-4 The alkyl group is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxyl, and provided that R 2 and R 3 At least one of is not hydrogen; or R 2 and R 3 Together with R 2 and R 3 The attached carbons are taken together to form an unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6 membered heterocyclic group, wherein when the C 3-6 When the cycloalkyl group and the 3-6 membered heterocyclic group are substituted, the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are independently substituted with 1 or 2 substituents selected from the group consisting of halogen and hydroxy; R 4 and R 5 are independently hydrogen, halogen, unsubstituted C 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 2-4 alkenyl; R 6 is hydrogen, unsubstituted C 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 3-4 alkenyl; and The prerequisite is R 4 、R 5 and R 6 At least one of is not hydrogen; or R 5 is hydrogen, halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 2-4 alkenyl; and R 4 and R 6 Taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring; X 1 CR A or N; R 7a 、R7b 、R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1-4 Haloalkyl, cyano or unsubstituted C 1-4 alkoxy; R 8 For hydrogen, -CH2OC(=O)-(unsubstituted C 1-4 alkyl), -CH2OC(=O)-O-(unsubstituted C 1-4 alkyl), -CH2-(α-amino acid), or -CH2-phosphate; and R A is hydrogen, halogen, unsubstituted C 1-4 a haloalkyl group or a cyano group.

[0163] In some embodiments, the CAM is selected from the compounds of Table A. Preferably, the CAM is in substantially pure form as a single compound; the CAM may be a combination containing one or more compounds disclosed herein as CAMs.

[0164] Table A

[0165] In some embodiments, the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetraazatricyclo[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-ethynyloxetane-3-yl)amino]methyl dihydrogen phosphate (Compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetane-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-trifluoropropane-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-cyclopropyloxyphenyl)-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-tetraazatricyclo[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-hydroxypropyloxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-one (Compound 27). ;

[0166] In some embodiments, the CAM is selected from any one of the CAMs disclosed in WO 2017 / 156255 A1; WO 2020 / 205934 A1; WO 2015 / 138895 A1; WO 2019 / 241292 A1; WO 2019 / 154343 A1; Zlotnick et al., 2002, A Small Molecule Inhibits and Misdirects Assembly of Hepatitis B Virus Capsids, J. Virol., 76:4848-4854; WO 2018 / 172852 A1; WO 2018 / 090862 A1; Deres et al., 2003, Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids, Science, 299:893-896; WO 2013 / 096744 A1; WO 2008 / 154817 A1; WO 2016 / 161268 A1; WO 2018 / 039531 A1; WO2013 / 144129 A1; WO 2014 / 033176; WO2020182990A1; WO2020182990A1; WO2022053010; WO2020125729; WO2022115384; US20220119385; WO2022081758; US20220000874; WO2021030278; WO2020247504; WO2020243199; WO2020214728; WO2020167984; WO2022266193; WO2023205653; or WO2023205645, each of which is hereby incorporated by reference in its entirety.

[0167] HBV surface antigen (HBsAg) lowering agents

[0168] In some embodiments, the HBsAg lowering agent is a small interfering RNA (siRNA). Examples of suitable siRNAs are described in US 2022 / 0177888 A1.

[0169] 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).

[0170] In some embodiments, the siRNA has a nucleic acid sequence as shown 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 shown in Table C below, with modifications as described in Table B.

[0171] Table B

[0172] Table C

[0173] In some embodiments, the HBsAg lowering agent is an siRNA selected from any one of the siRNAs disclosed in the following documents: WO 2016 / 077321 A1; WO 2020 / 163747 A1; US ​​2022 / 0177888 A1; US ​​2004 / 0127446 A1; WO 2018 / 191278 A2; US 8,202,979 B2; WO 2013 / 003520 A1; US ​​8,349,809 B2; or WO2023039005; each of which is hereby incorporated by reference in its entirety.

[0174] In some embodiments, the HBsAg lowering agent is an antisense oligonucleotide (ASO). In some embodiments, the ASO is selected from the group consisting of: GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche).

[0175] In some embodiments, the ASO has a nucleic acid sequence as shown in SEQ ID NO: 1. This sequence is shown below in Table E, with modifications as described in Table D.

[0176] Table D

[0177] Table E

[0178] In some embodiments, the HBsAg lowering agent is an ASO selected from any one of the ASOs disclosed in WO 97 / 003211; WO 2012 / 145697 A1; WO 2017 / 021385; WO 2018 / 053185 A1; US ​​10,793,859 B2; or US 11,466,274 B2; or WO2023177808; each of which is hereby incorporated by reference in its entirety.

[0179] In some embodiments, the HBsAg-lowering agent is a nucleic acid polymer (NAP). In some embodiments, the NAP is an S-antigen transport inhibitory oligonucleotide polymer (STOP). In some embodiments, the NAP is REP-2139 (Replicor).

[0180] In some embodiments, the HBsAg lowering agent is a NAP selected from any one of the NAPs disclosed in WO 2004 / 024919 A1; US ​​2004 / 0162253 A1; WO 2016 / 030863 A1; US ​​2020 / 0147124 A1; or WO 2021 / 198958 A1; each of which is hereby incorporated by reference in its entirety.

[0181] Delay period

[0182] In some embodiments, the initial administration of the second agent (e.g., CAM, siRNA, or ASO) is after a delay period after the initial administration of the first agent (e.g., CAM, siRNA, or ASO). In some embodiments, the initial administration of the second agent is after a delay period after the final administration of the first agent, for example, when the first agent is administered multiple times. In some embodiments, the initial administration of the second agent is after a delay period after the start of administration of the first agent. For example, in some embodiments, administration of the second agent is in addition to continuous treatment with the first agent.

[0183] In some embodiments, repeated administration is performed after the initial administration. For example, in some embodiments, the first or second agent is administered continuously after the initial administration of the first or second agent. In some embodiments, continuous administration refers to the administration of the first or second agent at regular repetitive intervals. For example, in some embodiments, continuous administration means once a day, twice a day, three times a day, four times a day, or five times a day or more, or a range administration constructed by any one of the aforementioned values. In some embodiments, continuous administration means once every other day, once every three days, once every four days, once every five days, once every six days, once a week, or once every other week, or a range administration constructed by any one of the aforementioned values. 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 preceding values.

[0184] In some embodiments, the initial administration of the second agent occurs after the first agent has been administered (in some embodiments, continuously) for a period of time (in other words, a delay period), e.g., at least two weeks, at least one month, at least six weeks, at least two months, at least three months, at least four months, at least five months, or at least six months.

[0185] In some embodiments, the initial administration of the second agent is after a delay period after the initial (such as start) administration of the first agent. In some embodiments, the delay period after the initial administration of the first agent is greater than about 1 day. In some embodiments, the delay period is greater 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, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 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 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, About 53 days, about 54 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 In some embodiments, the delay period is at least about 70 days. In some embodiments, the delay period is at least about 50 days.

[0186] 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 preceding values.

[0187] In some embodiments, an effective amount of an HBsAg lowering agent is administered to the subject, followed by administration of an effective amount of a capsid assembly regulator CAM to the subject. In some embodiments, the initial administration of the CAM is after a delay period following the initial administration of the HBsAg lowering agent. In some embodiments, the delay period is any one of the delay periods provided herein.

[0188] In some embodiments, the first or second medicament is administered multiple times, such as twice, three times, four times, five times, six times, seven times, etc., with an additional delay interval between each administration. The interval between administrations of the first or second medicament can be any of the above times listed for the delay period. For example, in some embodiments, the first medicament is administered at least three times at regular intervals before the second medicament is administered.

[0189] In some embodiments, the initial administration of the second agent occurs after the HBsAg level in the subject has been reduced by administration of the first agent. For example, in some embodiments, the delay period is determined based on the measurement of 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 10-fold reduction in HBsAg level is achieved compared to baseline. In other words, in such embodiments, (in other words, when a 10-fold reduction in HBsAg levels is achieved compared to baseline, addition of the HBsAg-lowering agent (such as siRNA or ASO) is initiated. In some embodiments, the delay period is extended until the subject's HBsAg levels are reduced by about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-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, compared to baseline. In some embodiments, the delay period is extended until the subject's HBsAg levels have decreased by about 0.5 log10, about 10-fold, or about 10-fold, compared to baseline. A decrease in HBsAg levels may be measured at a time point of 100 to 2000 s.i., 100 to 2000 s.i., 100 to 2000 s.i., 100 to 3000 s.i. Thus, in some embodiments, the method may comprise measuring the subject's HBsAg level periodically, such as daily, such as for comparison to a baseline.

[0190] In some embodiments, the initial administration of the second agent occurs after the HBsAg level in the subject has been reduced to a nadir by administering the first agent. In some embodiments, the nadir includes a period of at least one week, which includes at least one additional dose of the first agent, wherein the at least one additional dose does not cause a statistically significant decrease in HBsAg levels. In some embodiments, the delay period is extended until the subject's plasma HBsAg level reaches a nadir, for example, until the subject's plasma HBsAg level no longer continues to decrease, even after at least one, at least two, at least three, at least four, at least five or more administrations of the first agent, and 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 longer. In some embodiments, the delay period is extended until the subject's plasma HBsAg level no longer decreases further after at least two additional administrations of the first agent, and at least two weeks or at least three weeks.

[0191] In some embodiments, the delay period is determined based on the measurement of another HBV marker (such as HBV RNA, HBV DNA, HBeAg, HBcrAg). For example, in some embodiments, the delay period is extended until the level of the other HBV marker in the subject decreases compared to the pre-treatment baseline level of the other HBV marker. For example, in some embodiments, the delay period is extended until a 10-fold decrease in the level of the other HBV marker is achieved compared to the baseline. In other words, in such embodiments, (in other words, when a 10-fold reduction in the level of the other HBV marker is achieved compared to baseline, add-on of the HBsAg-lowering agent (such as siRNA or ASO) is initiated. In some embodiments, the delay period is extended until the subject's level of the other HBV marker is reduced by about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-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, compared to baseline. In some embodiments, the delay period is extended until the subject's level of the other HBV marker is reduced by about 0.5 log10, about 1 log10, about 1.5 log10, about 2.5 log10, about 3.5 log10, about 4.5 log10, about 5.5 log10, about 6.5 log10, about 7.5 log10, about 8.5 log10, about 9.5 log10, about 10.5 log10, about 10.5 log10, about 2.5 log10, about 3.5 log10, about 4.5 log10, about 5.5 log10, about 6.5 log10, about 7.5 log10, about 8.5 log10, about 9.5 log10, about 10.5 log A decrease in the level of an HBV marker may be measured in an amount of about 100 mg / dL, about 2 ...

[0192] Combination therapy

[0193] 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 HBV and / or HDV replication. Additional agents include, but are not limited to, interferons, nucleoside / nucleotide analogs, sequence-specific oligonucleotides (such as antisense oligonucleotides and siRNA), nucleic acid polymers (NAPs, such as those that reduce HBsAg levels, including 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 disoproxil, clavudine, 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 (incorporated herein by reference for the purpose of describing the siRNA compounds provided therein), such as an siRNA selected from SEQ. ID. NO. 1 to 617 and SEQ. ID. NO. 618.

[0194] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, can be administered with one or more additional pharmaceutical agents in a single pharmaceutical composition. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, can be administered with one or more additional pharmaceutical agents as two or more separate pharmaceutical compositions. In addition, the order of administration of a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutical agents can vary.

[0195] Example

[0196] Some aspects of the embodiments discussed above are disclosed in more 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 also fall within the scope of the present invention, as described above and in the claims.

[0197] Example 1

[0198] In vivo compound efficacy was evaluated in adeno-associated virus-hepatitis B virus (AAV-HBV) mice. Materials and methods are presented in Tables 1 to 4 below. Table F describes the nucleic acid sequence used for siRNA-1 (a type of siRNA). These sequences are described using the modified nucleotide notation presented in Table B.

[0199] Table F

[0200] Table 1 Subject details

[0201] Abbreviations: Grp = group; Vol = volume; No. An = number of animals; PO = oral gavage; SC = subcutaneous injection; BID = twice daily, 12 h / 12 ​​h interval.

[0202] Dosage regimens are shown in Figure 1 middle.

[0203] Table 2 Subject details

[0204] Table 3 Details of test articles and dosage formulations

[0205] Abbreviations: Grp = group; Vol = volume; Prep = preparation; Conc. = concentration; QW = once a week; BID = twice a day, 12 h / 12 ​​h interval.

[0206] Table 4 Details of test articles and dosage formulations

[0207] Test sample preparation: Compound 1 and siRNA-1 were provided as powders.

[0208] Prepare the vehicle (95% PEG-400, 5% copovidone, 100 mL): Weigh 5 g of copovidone (Plasdone S-630). Weigh 100 g of PEG-400. Add a small amount of copovidone to the PEG-400 while stirring continuously. Mix until a clear, colorless solution forms. Store the vehicle at room temperature for up to one week.

[0209] Preparation of Compound 1: Weigh the desired amount of test compound. Add the test compound to an appropriate amount of vehicle. Heat the mixture for 10 seconds, vortex for 10 seconds, and sonicate for 1 minute. Repeat the heating / vortexing / sonication process several times until a solution is obtained. The order of these steps may vary.

[0210] Preparation of siRNA-1 formulations: Add the required volume of vehicle to a vial to obtain a stock solution, vortex, and then incubate at 37°C for half an hour, vortexing again during the incubation period. Ensure that all powder has entered the solution. Check the clarity of the solution. Perform a quick spin centrifugation. Dilute the solution and measure the OD260 after dilution. Based on the actual concentration calculated from the OD value, dilute the stock solution to the target concentration. Measure the OD value of each formulation to obtain the actual concentration. Filter the formulation using a 0.22 μM PVDF filter. Aliquot the formulation and store at -20°C until use.

[0211] Real-time phase parameters: Twenty mice were selected and randomly divided into five groups for treatment based on plasma viral marker levels and body weight. Dead and / or moribund animals were inspected daily. Significant changes were recorded. Body weights were measured twice weekly from days 0 to 97 and weekly from days 98 to 189.

[0212] Vehicle (Group 01) and 55 mg / kg / dose of Compound 1 (Groups 02, 04, and 05) were administered twice daily by oral gavage from Days 0 to 97. siRNA-1 was injected subcutaneously at 5 mg / kg / dose on Days 0, 14, 42, and 70 for Groups 03 and 04, and on Days 70, 84, and 102 for Group 05.

[0213] Plasma samples (50 μL) were prepared from each mouse once weekly from day 0 to day 189, prior to dosing. The samples were used for quantitative determination of HBsAg, HBeAg, and HBV DNA. Mice were sacrificed on day 189.

[0214] Results: Results are displayed on Figures 2A to 4B In general, group 02 (CAM-A alone) was better than group 04 (CAM-A + siRNA co-administration); group 05 (siRNA addition) was the best. Figures 2A to 2B As shown in Figure 3, the rebound after CAM-A treatment was only partial, while the rebound after co-administration (Group 04) was close to the baseline. Figures 3A to 3B and Figures 4A to 4B As shown in Figure 3, CAM-A had a negative effect on the cell cycle, while a rebound was observed in the siRNA (Group 03) and co-administration (Group 04) groups. Figures 4A to 4B As shown, sustained HBeAg responses were observed in the additional group (Group 05), with no seroconversion and only a slight rebound at the last time point.

[0215] Example 2

[0216] In vivo compound efficacy was evaluated in adeno-associated virus-hepatitis B virus (AAV-HBV) mice. Materials and methods are presented in Tables 5 to 8 below. Table G describes the nucleic acid sequence used for siRNA-2 (an siRNA). These sequences are described using the modified nucleotide notation presented in Table B.

[0217] Table G

[0218] Table 5 Subject details

[0219] Abbreviations: Grp = group; Vol = volume; Freq = frequency; No. An = number of animals; PO = oral gavage; SC = subcutaneous injection; QOW = biweekly; BID = twice daily, 12 h / 12 ​​h interval.

[0220] The dosing regimen for the experiments involving siRNA (siRNA-2, SEQ ID NO: 4-5) + CAM-E (Compound 7) (Groups 01A, 02A, 03, 05, 06 and 07) is shown in Figure 5 middle.

[0221] The dosing regimen for the experiments involving siRNA (siRNA-2, SEQ ID NO: 4-5) + CAM-A (Compound 1) (Groups 01B, 02B, 04, and 08 to 10) is shown in Figure 9 middle.

[0222] Table 6 - Subject details

[0223] Table 7 - Test Article and Dosage Formulation Details

[0224] Abbreviations: Grp = group; Vol = volume; Freq = frequency; Conc. = concentration; QW = once a week; BID = twice a day, 12 h / 12 ​​h interval.

[0225] Table 8 - Test Article and Dosage Formulation Details

[0226] Compound 1, Compound 7, and siRNA-2 were provided as powders and formulated by Labcorp.

[0227] Prepare the vehicle (95% PEG-400, 5% copovidone, 100 mL) as follows. Weigh 5 g of copovidone (Plasdone S-630). Weigh 100 g of PEG-400. Add a small amount of copovidone to the PEG-400 while stirring continuously. Mix until a clear, colorless solution forms. Store the vehicle at room temperature for up to one week.

[0228] Formulations of Compound 1 and Compound 7 were prepared as follows. The desired amount of test compound was weighed. 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 process was repeated several times until a solution was obtained. The order of these steps may vary.

[0229] The formulation of siRNA-2 was prepared as follows. The required volume of vehicle was added to the bottle to obtain the stock solution, vortexed, and then placed at 37°C for half an hour and vortexed again during the incubation period. Make sure that all the powder goes into the solution. Check the clarity of the solution. If it appears cloudy or precipitated, place it at 50°C for half an hour. Perform a quick spin centrifugation, then dilute the solution and measure the OD260 after dilution. Based on the actual concentration calculated by the OD value, the stock solution was diluted to the target concentration. The OD value of each formulation was measured to obtain the actual concentration. The formulation was filtered using a 0.22μm PVDF filter. The formulation was aliquoted and stored at -20°C before use.

[0230] Pretreatment Parameters: Animal health was monitored during the pretreatment phase. Body weight was measured on day 0 before dosing. On day 0 before dosing, mice were bled for serum preparation (10 μL per mouse). Samples were stored at -70°C and later transferred for quantification of HBsAg, HBeAg, and HBV DNA.

[0231] Real-time phase parameters: Animals were assigned to cages using Excel tools based on serum HBsAg, HBeAg, and HBV DNA levels and body weight on pre-dose day 0. Low, medium, and high HBV titer values ​​were spread to equalize group means across groups.

[0232] Cages were inspected daily for dead and / or moribund animals, and significant changes were recorded. Body weights were measured twice weekly from day 0 to day 97. Additional body weight measurements were performed based on the interpretation of the study leader.

[0233] Vehicle was administered by oral gavage twice daily (12-hour intervals) at 5 mL / kg / dose in Groups 01A and 02A from Days 0 to 41, and in Group 1B from Days 0 to 97. siRNA-2 was administered by subcutaneous injection at 5 mL / kg / dose 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.

[0234] Compound 7 was administered by oral gavage twice daily (at 12-hour intervals) at 50 mg / kg / dose in Groups 03, 05, and 06 during Days 0 to 41, and in Group 07 during Days 14 to 41 at 5 mL / kg / dose.

[0235] Compound 1 was administered by oral gavage at 55 mg / kg / dose twice daily (at 12 hour intervals) in Groups 04, 08, and 09 during Days 0 to 97, and in Group 10 during Days 28 to 97.

[0236] Mice were bled once a week to prepare 25 μL of serum per mouse from day 0 to day 98. Samples were stored at −20° C. and later transferred for HBsAg, HBeAg, HBV DNA, and ALT detection.

[0237] Mice in groups 01A, 02A, 03, 05, 06, and 07 were sacrificed on day 42, and mice in groups 01B, 02B, 04, and 08 to 10 were sacrificed on day 98.

[0238] result: Figures 6A to 6B It was shown that when CAM-E compound 7 was combined with siRNA ( combo ) antagonistic effect on HBsAg reduction. Sequential dosing regimen (compound 7->combo ( D14- )and siRNA-2->combo ( D14- ) showed slight improvement (less antagonism). Other sequential regimens may be able to completely overcome antagonism. 7A to 7B The HBeAg readings shown in showed a more limited antagonistic effect of the combination on this parameter, likely due to the smaller magnitude of HBeAg reduction. Figure 8A and Figure 8B As shown, no clear antagonistic effect or incremental benefit of the sequential regimen was observed on HBV DNA readouts.

[0239] like FIG. 10A to FIG. 10B As shown, compared with siRNA alone ( siRNA-2 ( D0-14-35-49)) compared to the combination of CAM-A+siRNA ( combo ) showed no antagonistic effect on the reduction in HBsAg measurements and even caused an additional decrease 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 showed an enhancement of siRNA efficacy. The most favorable scenario consisted of adding siRNA to CAM-A (compound 1- >combo ( D70- ) which caused an additional decrease in serum HBsAg levels from day 77 onwards. A similar trend was observed for HBeAg ( Figures 11A to 11B For HBV DNA readings ( FIG. 12A to FIG. 12B ), the differences between regimens were limited, which may be due to the fact that CAM-A monotherapy already induced profound HBV DNA reduction.

[0240] Example 3

[0241] In the following examples, initial treatment with siRNA followed by CAM addition was tested in mice.

[0242] The study design is described in Table 9 below.

[0243] Table 9 – Study design

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

[0245] Results: As Figure 13A and Figure 13B As shown, administration of siRNA followed by CAM-E (Compound 6) resulted in a good reduction in HBV DNA, even greater than that of the siRNA-only group (Group 4). Figure 14A 、 Figure 14B 、 Figure 15A and Figure 15B As shown, by day 98, HBsAg / HBeAg reduction was greater with siRNA+CAM-E addition compared to CAM-E alone, and no antagonistic effect was observed with siRNA+CAM-E addition (Group 5) compared to siRNA alone, which was different from the antagonistic effect observed in the co-administration group in Example 2.

[0246] like Figure 16A and Figure 16BAs shown, the CAM-A (Compound 2) alone group caused a good reduction in HBV DNA, while the siRNA + CAM-A addition group (Group 6) caused an even greater reduction in HBV DNA. Figure 17A 、 Figure 17B 、 Figure 18A and Figure 18B As shown, by day 98, siRNA+CAM-A addition resulted in greater reduction in HBsAg / HBeAg compared to CAM-A alone, and no antagonistic effect was observed with siRNA+CAM-A addition (Group 6) compared to siRNA alone.

[0247] Discussion: The above results indicate that sequential delayed dosing can unexpectedly resolve any antagonistic effects observed with simultaneous dosing, such as observed in the co-administered groups of Example 2.

[0248] Other considerations

[0249] This document includes headings for reference and to assist in locating various sections. These headings are not intended to limit the scope of the concepts described herein. Such concepts may have applicability throughout this specification.

[0250] The entire text of each patent, patent application, publication, and document cited herein is hereby incorporated by reference. Citation of the aforementioned patents, patent applications, publications, and documents is not an admission that any of them are relevant prior art, nor does it constitute any admission as to the contents or dates of these publications or documents. Their citation does not constitute a search for relevant disclosures. All statements regarding the dates or contents of documents are based on the available information and are not admissions as to their accuracy or correctness.

[0251] In the foregoing description, specific details are given to provide a thorough understanding of the examples. However, it will be understood by one of ordinary skill in the art that the examples may be practiced without these specific details.

[0252] 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 claims.

[0253] The methods disclosed herein include one or more steps or actions for implementing the described methods. Method steps and / or actions may be interchangeable with one another without departing from the scope of this disclosure. In other words, unless the correct operation of the described methods requires a specific order of steps or actions, the order and / or use of specific steps and / or actions may be modified.

[0254] In at least some of the described embodiments, one or more elements used in an embodiment may be used interchangeably in another embodiment, unless such replacement is technically infeasible. It will be understood by those skilled in the art that various other omissions, additions, and modifications may be made to the above-described methods and structures without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter as defined by the appended claims.

[0255] For substantially any plural or singular term used herein, one skilled in the art can translate from the plural to the singular or from the singular to the plural as is appropriate to the context or application. For sake of clarity, the various singular / plural permutations may be expressly set forth herein.

[0256] The embodiments described herein as being illustrative in nature may be practiced without any elements not specifically disclosed herein. Thus, for example, in each case herein, any one of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with any one of the other two terms. The terms and expressions employed are used as descriptive, rather than restrictive, terms and expressions, and the use of such terms and expressions does not exclude any equivalents of the features shown and described or their parts, and various modifications are possible within the scope of the claimed technology. The term "one" or "a kind of" may refer to one or more elements in the element it modifies (e.g., "a reagent" may refer to one or more reagents), unless the context clearly describes one or more elements in the element. As used herein, the term "about" or "approximately" refers to a value within 10% of a basic parameter (i.e., plus or minus 10%), and the term "about" or "approximately" is used at the beginning of a string of values ​​to modify each value (i.e., "about 1, 2, and 3" refers to about 1, about 2, and about 3). For example, a weight of "about 100 grams" may include a weight between 90 grams and 110 grams. In addition, 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 ​​thereof (e.g., 54%, 85.4%). Therefore, it should be understood that although the present technology has been specifically disclosed through representative embodiments and optional features, those skilled in the art may make modifications and variations to the concepts disclosed herein, and such modifications and variations are considered to be within the scope of the embodiments.

[0257] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0258] As will be understood by those skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily considered to fully describe and enable the same range to be decomposed into at least equal halves, thirds, quarters, fifths, or tenths. As non-limiting examples, each range discussed herein can be easily decomposed into lower thirds, middle thirds, and upper thirds, etc. As will be understood by those skilled in the art, all languages ​​such as "up to," "at least," "greater than," "less than," etc. include the narrated numbers and refer to ranges that can subsequently be decomposed into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to a group having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to a group having 1, 2, 3, 4, or 5 articles, etc.

[0259] All published patents, published patent applications, and other non-patent publications cited and described herein are hereby incorporated by reference in their entirety. Furthermore, although the foregoing has been described in some detail by way of illustration and example for the purposes of clarity and understanding, it will be understood by those skilled in the art that many and various modifications may be made without departing from the essence of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternatives that fall within the true scope and essence of the present disclosure.

Claims

1. A method of treating hepatitis B virus (HBV) and / or hepatitis D virus (HDV) 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) lowering 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) a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; and wherein the initial administration of the second medicament is after a delay period after the initial administration of the first medicament.

2. The method according to claim 1, wherein the method is a method for treating HBV infection.

3. The method of claim 1, wherein the method is a method of treating HDV infection.

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

5. The method of any one of claims 1 to 3, wherein the first agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein the second agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof. 6 . The method according to 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 according to 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 according to any one of claims 1 to 7, wherein the HBsAg lowering agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

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

10. The method according to any one of claims 1 to 9, wherein the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetraazatricyclo[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 dihydrogen phosphate (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-cyclopropyloxyphenyl)-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-tetraazatricyclo[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), or a pharmaceutically acceptable salt of any one of the foregoing.

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

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. The method of claim 11, wherein the siRNA has a nucleic acid sequence as shown 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 lowering agent is an ASO.

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. The method of claim 14, wherein the ASO has the nucleic acid sequence shown in SEQ ID NO:

1.

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

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

19. The method of claim 18, wherein the nadir comprises a period of at least one week, the period comprising 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. The method of any one of claims 1 to 19, wherein the initial administration of the second agent occurs after the first agent has been administered continuously for at least one month.

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

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

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

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

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

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

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

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

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

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

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 a nadir.

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 sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7; or wherein (b) the first agent is an siRNA having the nucleic acid sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is Compound 4 or a pharmaceutically acceptable salt thereof.

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. The method of claim 33, wherein the additional agent is selected from the group consisting of recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clavudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil and an additional siRNA, or a pharmaceutically acceptable salt of any one of the foregoing.

35. A method of maintaining low plasma HBsAg levels in a subject suffering from HBV and / or HDV infection, 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) lowering 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) a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; wherein the initial administration of the second medicament is after a delay period after the initial administration of the first medicament.

36. The method of claim 35, wherein the method is a method of treating HBV infection.

37. The method of claim 35, wherein the method is a method of treating HDV infection.

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

39. The method of any one of claims 35 to 37, wherein the first agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein the second agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof.

40. The method of claim 36, wherein the first agent is a short interfering RNA (siRNA), and wherein 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 either of the foregoing.

41. 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 wherein the second agent is a short interfering RNA (siRNA).

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 sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7; or wherein (b) the first agent is an siRNA having the nucleic acid sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is Compound 4 or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 35 to 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. The method of claim 43, wherein the additional agent is selected from the group consisting of recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clavudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil and an additional siRNA, or a pharmaceutically acceptable salt of any one of the foregoing.

45. An improved method for treating hepatitis B virus and / or hepatitis D virus infection in a subject who has initiated therapy with a first agent selected from the group consisting of: (i) a HBV surface antigen (HBsAg) lowering agent or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, the improved method 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) a HBsAg lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; wherein the initial administration of the second medicament is after a delay period after the initial administration of the first medicament.

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

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

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

49. 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 wherein the second agent is a HBsAg lowering agent or a pharmaceutically acceptable salt thereof.

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

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

54. The improved method of any one of claims 45 to 53, wherein the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)-11-methyl-8-oxo-2,3,7,12-tetraazatricyclo[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 dihydrogen phosphate (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-cyclopropyloxyphenyl)-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-tetraazatricyclo[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), or a pharmaceutically acceptable salt of any one of the foregoing.

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

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. The improved method of claim 55, wherein the siRNA has a nucleic acid sequence as shown 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. The improved method of any one of claims 45 to 54, wherein the HBsAg lowering agent is an ASO.

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. The improved method of claim 58, wherein the ASO has a nucleic acid sequence as shown in SEQ ID NO:

1.

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

62. The improvement according to any one of claims 45 to 61, wherein the delay period is greater than about 50 days.

63. The improvement according to any one of claims 45 to 62, wherein the delay period is greater than about 2 months.

64. The improvement according to any one of claims 45 to 63, wherein the delay period is between about 21 days and about 168 days.

65. The improvement according to any one of claims 45 to 64, wherein the delay period is between about 28 days and about 91 days.

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

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

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

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

70. The improved method according to any one of claims 45 to 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 sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7; or wherein (b) the first agent is an siRNA having the nucleic acid sequence shown in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is Compound 4 or a pharmaceutically acceptable salt thereof.

71. The improved method of any one of claims 45 to 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. The improved method of claim 72, wherein the additional agent is selected from the group consisting of recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clavudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil and an additional siRNA, or a pharmaceutically acceptable salt of any one of the foregoing.

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