Drug combination comprising a TLR7 agonist

Abstract

A pharmaceutical combination comprising a TLR7 agonist. Specifically, a pharmaceutical combination and use of a compound of formula I as a TLR7 agonist in combination with entecavir for the treatment of hepatitis B virus infection, and the pharmaceutical combination has a good effect against hepatitis B virus infection.

Description

[0001] Citation of Related Applications

[0002] This application claims the priority and benefits of Chinese Patent Application No. 201910933558.8, filed with the State Intellectual Property Office of the People's Republic of China on September 29, 2019, the entire content of which is hereby incorporated by reference in its entirety into the text. Technical Field

[0003] This application belongs to the field of medicinal chemistry and relates to a drug combination comprising a TLR7 agonist. Specifically, it relates to a drug combination and use of a compound of Formula I as a TLR7 agonist in combination with entecavir for the treatment of hepatitis B virus infection. Background Art

[0004] According to statistics from the World Health Organization, approximately 257 million people worldwide are infected with hepatitis B virus (HBV). If hepatitis patients cannot receive treatment, they will face long-term fatal diseases such as liver failure, cirrhosis, and liver cancer.

[0005] Currently, the conventional drugs licensed for the treatment of chronic hepatitis B include nucleoside (acid) compounds and interferons. Nucleoside (acid) drugs, such as entecavir, can inhibit HBV DNA replication.

[0006] Toll-like receptors are expressed on a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMPs) expressed by microbial pathogens or damage-associated molecular patterns (DAMPs) released by necrotic cells. Stimulation of Toll-like receptors by the corresponding pathogen-associated microbial patterns (PAMPs) or damage-associated molecular patterns (DAMPs) triggers a signal cascade leading to the activation of transcription factors such as AP-1, NF-κB, and interferon regulatory factors (pulse response functions). This results in a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines, and effector cytokines, thereby generating an immune response. To date, 13 Toll-like receptors have been discovered in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are mainly expressed on the cell surface, and Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different Toll-like receptors recognize different pathogen-derived ligands. For Toll-like receptor 7 (TLR7), it is mainly expressed by plasmacytoid dendritic cells (pDC) and ligand recognition induces the secretion of interferon α (IFN-α). Some TLR7 agonists have been reported, such as Imiquimod, resiquimod, GS-9620, etc. WO2016023511 and WO2017076346 (the contents of which are incorporated herein by reference in their entirety) disclose a new class of TLR7 agonists, and the compounds exhibit good biological activity and selectivity.

[0007] Although there are many treatment options for patients infected with hepatitis B virus, more effective therapeutic agents are still needed for clinical use. DETAILED DESCRIPTION OF THE INVENTION

[0009] On the one hand, the present application provides a pharmaceutical combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, solvate thereof.

[0010] On the other hand, the present application also provides the use of the pharmaceutical combination of the present application in the preparation of a medicament for the treatment of hepatitis B virus infection. The present application also provides a method for treating hepatitis B virus infection, which comprises administering an effective amount of the pharmaceutical combination of the present application to an individual in need thereof. The present application also provides a pharmaceutical combination for the treatment of hepatitis B virus infection. The present application also provides the use of the pharmaceutical combination of the present application for the treatment of hepatitis B virus infection.

[0011] On the one hand, the present application provides a pharmaceutical combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, solvate thereof, wherein the compound of formula I is as follows:

[0012]

[0013] Wherein,

[0014] L1 is selected from -O-;

[0015] L2 is selected from -CH2-, wherein the above -CH2- is optionally substituted by R4;

[0016] R1 is selected from hydrogen, or C 1-10 alkyl, wherein the above C 1-10 alkyl is optionally substituted by R5;

[0017] R2 is selected from hydrogen, cyano, -COOH, or -CONH2, wherein the above -COOH, and -CONH2 are optionally substituted by R6;

[0018] B is selected from a 6-10 membered aryl, or a 5-10 membered heteroaryl;

[0019] L3 is selected from C 0-6 alkylene, or imino, wherein the above C 0-6 alkylene, and imino are optionally substituted by R7;

[0020] R3 is selected from hydrogen, amino, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the above amino, C 1-10 alkyl, C 3-10The cycloalkyl group, 3- to 10-membered hetero cycloalkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group is optionally substituted by R8, or,

[0021] R3 and L3 together with adjacent atoms on the B ring form a saturated or unsaturated 5- to 8-membered ring, and the 5- to 8-membered ring is optionally substituted by R9;

[0022] n is 0, 1, 2, 3, 4 or 5;

[0023] R4, R5, R6, R7, R8, and R9 are each independently selected from halogen, cyano, hydroxy, mercapto, amino, -R, -OR, =O, -SR, -NHR, -NR2; R is independently selected from C 1-8 alkyl, C 3-8 cycloalkyl group, 3- to 8-membered hetero cycloalkyl group, 6- to 8-membered aryl group, 5- to 8-membered heteroaryl group.

[0024] In some embodiments of the compound of formula I, L2 is selected from -CH2-.

[0025] In some embodiments of the compound of formula I, R1 is selected from C 1-6 alkyl, wherein the above C 1-6 alkyl is optionally substituted by one or more R5.

[0026] In some embodiments of the compound of formula I, R2 is selected from hydrogen, cyano, or -CONH2, wherein the above -CONH2 is optionally substituted by one or more R6.

[0027] In some embodiments of the compound of formula I, B is selected from 6- to 7-membered aryl group, or 5- to 7-membered heteroaryl group. In some embodiments of the compound of formula I, B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, furyl, oxazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or triazolyl. In some embodiments of the compound of formula I, B is selected from phenyl, pyridyl, or thiazolyl.

[0028] In some embodiments of the compound of formula I, L3 is selected from C 0-6 alkylene, wherein the above C 0-6 alkylene is optionally substituted by one or more R7.

[0029] In some embodiments of the compound of formula I, R3 is selected from hydrogen, amino, C 1-6 alkyl, C 3-8 cycloalkyl group, 3- to 8-membered hetero cycloalkyl group, 6- to 8-membered aryl group, or 5- to 8-membered heteroaryl group, wherein the above amino, C 1-6 alkyl, C 3-8A cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a 6- to 8-membered aryl group, or a 5- to 8-membered heteroaryl group is optionally substituted by one or more R8; or R3, L3 and adjacent atoms on the B ring together form a saturated or unsaturated 5- to 8-membered ring, and the 5- to 8-membered ring is optionally substituted by one or more R9. In some embodiments of the compound of formula I, R3 is selected from hydrogen, amino, C 1-6 alkyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl, diazepanyl, or 2-oxa-5-azabicyclo[2.2.1]heptyl, wherein the above-mentioned amino, C 1-6 alkyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl, diazepanyl, or 2-oxa-5-azabicyclo[2.2.1]heptyl is optionally substituted by one or more R8; or R3, L3 and adjacent atoms on the B ring together form a saturated or unsaturated 6-membered ring, and the 6-membered ring is optionally substituted by one or more R9.

[0030] In some embodiments of the compound of formula I, R4, R5, R6, R7, R8, and R9 are each independently selected from halogen, -R, -OR, or =O.

[0031] In some embodiments of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from:

[0032] 2-Butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0033] 2-Butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0034] 7-(3-(Aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0035] 2-Butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0036] 2-Butoxy-7-(4-((3,3-difluoropyrrolidin-1-yl)methyl)benzyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0037] 2-Butoxy-7-(4-((3-fluoropyrrolidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0038] 1-(4-((4-Amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)benzyl)pyrrolidin-3-ol;

[0039] 2-Butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0040] 2-Butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0041] 2-Butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0042] 2-Butoxy-7-(4-((dimethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0043] 2-Butoxy-7-(4-((diethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0044] 2-Butoxy-7-(4-((dipropylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0045] 7-(4-(azetidin-1-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0046] 2-Butoxy-7-(4-((3-methoxyazetidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0047] 2-Butoxy-7-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0048] 2-Butoxy-7-(4-((2,6-dimethylmorpholinyl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0049] 7-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0050] 2-Butoxy-7-(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0051] 2-Butoxy-7-(4-((4-isopropylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0052] 2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0053] 2-Butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0054] 2-Butoxy-7-(3-(2-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0055] 2-Butoxy-7-(4-(1-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0056] 2-Butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0057] 2-Butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0058] 1-(4-((4-Amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one;

[0059] 7-Benzyl-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0060] 2-(2-Methoxyethoxy)-7-((6-methylpyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0061] 7-((5-Chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0062] 2-(2-Methoxyethoxy-)-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0063] 1-(4-((4-Amino-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one;

[0064] 2-Butoxy-7-((5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0065] 4-Amino-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile;

[0066] 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile;

[0067] 4-Amino-2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile;

[0068] 4-Amino-2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile;

[0069] 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide;

[0070] 2-Butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0071] 2-Butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0072] 2-Butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0073] 2-Butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0074] 2-Butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0075] 2-Butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0076] 2-Butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;

[0077] 2-Butoxy-7-((2-(pyrrolidin-1-ylmethyl)thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof, or 2-butoxy-7-((2-(pyrrolidin-1-ylmethyl)thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments of the present application, the entecavir solvate is selected from entecavir hydrate. In some embodiments, the entecavir hydrate is selected from entecavir 0.5-2 hydrates. The entecavir hydrate is selected from entecavir monohydrate.

[0080] In some embodiments of the present application, the pharmaceutically acceptable salt of entecavir is selected from maleate. In some embodiments of the present application, the pharmaceutically acceptable salt of entecavir is selected from monomaleate.

[0081] In some embodiments of the present application, entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.

[0082] In some embodiments of the present application, the pharmaceutical combination comprises 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof, and entecavir or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical combination described in the present application comprises 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, or its maleate, trifluoroacetate, and entecavir or a pharmaceutically acceptable salt, hydrate thereof. In some embodiments, the pharmaceutical combination described in the present application comprises 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine and entecavir or its monohydrate.

[0083] In some embodiments of the present application, the drug combination comprises 2-butoxy-7-((2-(pyrrolidin-1-ylmethyl)thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof, and entecavir or a solvate thereof. In some embodiments, the drug combination described in the present application comprises 2-butoxy-7-((2-(pyrrolidin-1-ylmethyl)thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine and entecavir maleate monohydrate.

[0084] In some embodiments of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof in the drug combination can be administered once a day, twice a day, once every two days, once every three days, once every four days, or once every five days, with each administration being 0.0001 to 20 mg / kg by weight (calculated based on the weight of the compound of formula I).

[0085] In some embodiments of the present application, entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination can be administered once a day, twice a day, or once every two days, with each administration being a 0.5 mg or 1.0 mg dosage (calculated based on the weight of entecavir).

[0086] In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is 0.005 mg to 10.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is 0.05 mg to 5.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is 0.10 mg to 2.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is 0.25 mg to 2.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is 0.5 mg to 1.0 mg.

[0087] In some embodiments of the present application, the ratio (by weight) of the compound of formula I or its pharmaceutically acceptable salt to the average daily dose of entecavir or its pharmaceutically acceptable salt and solvate is selected from 10:1 to 1:10. In some embodiments, the ratio (by weight) of the compound of formula I or its pharmaceutically acceptable salt to the average daily dose of entecavir or its pharmaceutically acceptable salt and solvate is selected from 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7, 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9, 1:8, 1:8.1, 1:8.2, 1:8.3, 1:8.4, 1:8.5, 1:8.6, 1:8.7, 1:8.8, 1:8.9, 1:9, 1:9.1, 1:9.2, 1:9.3, 1:9.4, 1:9.5, 1:9.6, 1:9.7, 1:9.8, 1:9.9, 1:10 or a range formed by any of the above ratios. In some embodiments, the ratio (by weight) of the compound of formula I or its pharmaceutically acceptable salt to the average daily dose of entecavir or its pharmaceutically acceptable salt and solvate is preferably selected from 1:1.5 to 1:4, 1:1.6 to 1:3.8, 1:1.8 to 1:3.8, 1:1.8 to 1:3.6 or 1:2 to 1:3.5.

[0088] In some embodiments of the present application, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt and entecavir or its pharmaceutically acceptable salt and solvate in the fixed combination are present in the same solid pharmaceutical composition.

[0089] In some embodiments of the present application, the drug combination is a non-fixed combination. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the non-fixed combination are each in the form of a solid pharmaceutical composition. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the non-fixed combination are each in the form of a solid pharmaceutical composition, and the solid pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof and the solid pharmaceutical composition of entecavir or a pharmaceutically acceptable salt or solvate thereof are present in the same sachet. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the non-fixed combination are each in the form of a solid pharmaceutical composition, and the solid pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof and the solid pharmaceutical composition of entecavir or a pharmaceutically acceptable salt or solvate thereof are not present in the same sachet.

[0090] In some embodiments of the present application, the solid pharmaceutical composition is selected from tablets or capsules.

[0091] On the other hand, the present application also provides the use of the drug combination of the present application in the preparation of a drug for the treatment of hepatitis B virus infection. The drug combination is as described above.

[0092] On the other hand, the present application also provides a method for treating hepatitis B virus infection, which comprises administering an effective amount of the drug combination of the present application to an individual in need. The drug combination is as described above.

[0093] On the other hand, the present application also provides the drug combination of the present application for the treatment of hepatitis B virus infection. The drug combination is as described above.

[0094] On the other hand, the present application also provides the use of the drug combination of the present application for the treatment of hepatitis B virus infection. The drug combination is as described above.

[0095] In some embodiments of the present application, the present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the preparation of a drug for the treatment of hepatitis B virus infection, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof are separately prepared into pharmaceutical compositions.

[0096] In some embodiments of the present application, the present application also provides a kit for treating hepatitis B virus infection, which comprises: (a) a first pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient; and (b) a second pharmaceutical composition containing entecavir or a solvate thereof as an active ingredient; and optionally (c) instructions for the combined use of the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, solvate thereof.

[0097] The compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof

[0098] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the compound of formula A or a pharmaceutically acceptable salt thereof:

[0099]

[0100] The compound of formula A belongs to the prior art, and its chemical name is 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine. Its preparation method and chemical properties can be referred to WO2016023511.

[0101] In some embodiments, the pharmaceutically acceptable salt of the compound of formula A is selected from maleate or fumarate.

[0102] In some embodiments, the pharmaceutical composition of the compound of formula A or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, preferably tablets or capsules.

[0103] In some embodiments, the compound of formula A or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the pharmaceutical composition is a pharmaceutical composition with a single dose of 0.01 mg to 10 mg, preferably selected from pharmaceutical compositions with a single dose of 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, 10.0 mg or a pharmaceutical composition within the range formed by any of the above values.

[0104] Entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutical composition thereof

[0105] As used in the present application, the chemical name of entecavir is 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one, and it has the following structural formula:

[0106]

[0107] In some embodiments, the entecavir includes its pharmaceutically acceptable salts, and the pharmaceutically acceptable salts are selected from maleates. In some embodiments, the pharmaceutically acceptable salt of entecavir is selected from monomaleate.

[0108] In some embodiments, the entecavir includes its solvates, and the solvates are selected from entecavir hydrates. In some embodiments, the entecavir hydrates are selected from entecavir 0.5-2 hydrates. In some embodiments, the entecavir hydrates are selected from entecavir monohydrate.

[0109] In some embodiments, the entecavir is selected from entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.

[0110] In some embodiments, entecavir or its pharmaceutically acceptable salts, its solvates are in the form of a pharmaceutical composition. Preferably, the pharmaceutical composition is selected from solid pharmaceutical compositions. The solid pharmaceutical composition is preferably selected from tablets or capsules.

[0111] In some embodiments, the pharmaceutical composition of entecavir or its pharmaceutically acceptable salts, its solvates is selected from pharmaceutical compositions with a single dose of 0.01 mg to 5 mg, preferably from pharmaceutical compositions with a single dose of 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg or a pharmaceutical composition within the range formed by any of the above values.

[0112] As used in the present application, the entecavir or its pharmaceutically acceptable salts, its solvates, or its pharmaceutical composition may be selected from commercially available products.

[0113] Definitions and explanations

[0114] Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indeterminate or unclear without a special definition, but should be understood according to the ordinary meaning in the art.

[0115] As used in the present application, the compound of formula I or its pharmaceutically acceptable salt is a TLR7 agonist.

[0116] As used in the present application, the chemical name of entecavir is 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one, and it has the following structural formula:

[0117]

[0118] As used in the present application, partial structural formulas and chemical names of the compound of Formula I or a pharmaceutically acceptable salt thereof are shown as follows:

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] As used in the present application, the compound of Formula I includes its non-salt form (for example, free acid or free base), and also includes its pharmaceutically acceptable salts, and both the non-salt and the salts are within the scope of protection of the present application. For example, the pharmaceutically acceptable salts of the compound of Formula I may be hydrochloride, maleate or fumarate.

[0125] As used in the present application, the entecavir includes its non-solvate form and also includes its solvate form, and both the non-solvate and the solvate are within the scope of protection of the present application. When selected from the solvate form, the molar ratio of the compound to the solvent may be selected from 1:0.5, 1:1, 1:1.5, 1:2 or the range formed by any endpoints, such as 1:0.5 to 1:2, 1:0.5 to 1:1.5, or 1:1 to 1:1.5. For example, the entecavir is in the form of a non-solvate. For example, the entecavir is in the form of a hydrate. For example, the entecavir is in the form of a monohydrate.

[0126] As used in the present application, the dose is calculated based on the weight of the free form of the compound, and the free form refers to the non-salt compound and the non-solvate.

[0127] The term "substituted" or "being substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0128] The term "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, ethyl is "optionally" substituted by halogen, which means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.) or completely substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0129] The C in this article m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0130] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted by 2 Rs, each R has independent options.

[0131] When the number of a linking group is 0, such as -(CH2)0-, it means that this linking group is a covalent bond.

[0132] When a substituent's bond cross-links to two atoms on a ring, this substituent can bond to any atom on this ring. For example, the structural unit indicates that its substitution can occur at any position on cyclohexyl or cyclohexadiene.

[0133] The term "halo" or "halogen" means fluorine, chlorine, bromine and iodine.

[0134] The term "hydroxy" refers to the -OH group.

[0135] The term "cyano" refers to the -CN group.

[0136] The term "mercapto" refers to the -SH group.

[0137] The term "amino" refers to the -NH2 group.

[0138] The term "alkyl" refers to the general formula C n H 2n+1hydrocarbyl group. The alkyl group can be straight-chain or branched-chain. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moieties of alkoxy, monoalkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups (i.e., alkyl) have the same definition as described above.

[0139] The term "alkoxy" refers to -O-alkyl.

[0140] The term "cycloalkyl" refers to a carbocyclic ring that is completely saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0141] The term "cyclohydrocarbyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbyl group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cyclohydrocarbyl group can be a monocyclic, fused polycyclic, bridged, or spiro ring structure. Non-limiting examples of cyclohydrocarbyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl, etc.

[0142] The term "heterocyclic group" refers to a non-aromatic ring that is completely saturated or partially unsaturated (but not completely unsaturated heteroaromatic) and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

[0143] The term "heteroalkyl" refers to a cyclic group that is completely saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heteroalkyls include, but are not limited to, oxiranyl, thiiranyl, aziridinyl; non-limiting examples of 4-membered heteroalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl; examples of 5-membered heteroalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl; examples of 6-membered heteroalkyls include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl; examples of 7-membered heteroalkyls include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred is a monocyclic heteroalkyl having 5 or 6 ring atoms.

[0144] The term "heterocyclic hydrocarbyl" refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system group, wherein some of the ring atoms are heteroatoms selected from N, O, S(O) n (where n is 0, 1 or 2), and the remaining ring atoms are C. Such rings can be saturated or unsaturated (e.g., having one or more double bonds), but do not have a fully conjugated π-electron system. Examples of 3-membered heterocyclic hydrocarbyls include, but are not limited to, oxiranyl, thiiranyl, aziridinyl; examples of 4-membered heterocyclic hydrocarbyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl; examples of 5-membered heterocyclic hydrocarbyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl; examples of 6-membered heterocyclic hydrocarbyls include, but are not limited to, piperidinyl, tetrahydropyrazolyl, tetrahydrothienyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,2-, 1,4-dithianyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl; examples of 7-membered heterocyclic hydrocarbyls include, but are not limited to, azepanyl, oxepanyl, thiepanyl, oxaazabicyclo[2.2.1]heptyl and azaspiro[3.3]heptyl, etc.

[0145] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl can have 6 - 20 carbon atoms, 6 - 14 carbon atoms or 6 - 12 carbon atoms. Non-limiting examples of aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

[0146] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 8-membered ring or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.

[0147] The compounds of the present application can be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0148] The term "administer" means physically introducing a composition containing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0149] The term "treatment" generally refers to obtaining the desired pharmacological and / or physiological effect. This effect can be therapeutic depending on partially or completely stabilizing or curing the disease and / or the side effects resulting from the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0150] The term "effective amount" means the amount of the compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present application constituting a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0151] The term "individual" can be a mammal. In some embodiments, the subject is a mouse. In some embodiments, the subject is a human.

[0152] As used in this application, the compound of formula I or a pharmaceutically acceptable salt thereof can be administered by any applicable route and method, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof is from about 0.0001 to 20 mg / kg body weight / day, including but not limited to, for example, from 0.001 to 10 mg / kg body weight / day. The dosing frequency of the compound of formula I or a pharmaceutically acceptable salt thereof is determined by the individual needs of the patient, including the severity, response to the disease, any treatment-related toxicity, the age and health status of the patient, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, in which over a period of several days, the subject receives a daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof, followed by a period of several days or more during which the patient does not receive a daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0153] Entecavir can be administered by a variety of routes, which include but are not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, by topical administration, subcutaneous, intradermal, intraarticular, intraperitoneal, and intrathecal. In some particular embodiments, it is administered orally. The amount of entecavir administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the patient. For example, the daily dose of entecavir administered can be from 0.005 mg to 10.0 mg. Entecavir can be administered once or more times a day. In some embodiments, entecavir is administered once a day as an oral solid formulation.

[0154] The term "about" should be understood to include within three standard deviations of the mean or within the standard tolerances in a particular field. In certain embodiments, about should be understood as not exceeding a variation of 0.5. "About" modifies all the values enumerated thereafter. For example, "about 1, 2, 3" means "about 1", "about 2", "about 3".

[0155] The term "drug combination" refers to the use of two or more active ingredients simultaneously, concurrently, or sequentially.

[0156] The term "fixed combination" refers to the active ingredients (such as a TLR7 agonist or entecavir) being administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition, or formulation. In some embodiments, for example, it is present in the same tablet, the same capsule, or the same sachet.

[0157] The term "non-fixed combination" refers to two or more active ingredients administered to an individual simultaneously, concurrently or sequentially without a specific time limit as independent entities (e.g., pharmaceutical compositions, pharmaceutical formulations), wherein the active ingredients administered to the individual reach a therapeutically effective amount level. Examples of non-fixed combinations that can be cited are combination therapies, such as administering two, three or more active ingredients. In a non-fixed combination, each of the active ingredients can be packaged, sold or administered as a completely independent pharmaceutical composition. The "non-fixed combination" also includes the combined use between "fixed combinations", or between "fixed combinations" and independent entities of any one or more active ingredients.

[0158] The term "pharmaceutical composition" refers to a mixture composed of one or more compounds of the present application, or their pharmaceutical combinations, or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application or their pharmaceutical combinations to a subject.

[0159] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0160] The term "pharmaceutically acceptable salt" or "medicinal salt" refers to the salts of the compounds of the present application within the definition of "pharmaceutically acceptable".

[0161] Unless otherwise specifically stated, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specifically stated, the word "a" or "an" means "at least one" or "at least one kind". Unless otherwise stated, the use of "or" means "and / or".

[0162] In this article, unless otherwise stated, the terms "comprising, including and containing" or equivalents are open-ended expressions, meaning that other unspecified elements, components and steps can be covered in addition to the listed elements, components and steps.

[0163] For the purposes of description and disclosure, all patents, patent applications and other established publications are hereby expressly incorporated herein by reference. These publications are provided only because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representation of the content of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the content of these documents. Moreover, in any country, any reference to these publications in this application does not constitute an admission that the publication has become part of the common general knowledge in the art.

[0164] Route of administration

[0165] The following does not limit the administration mode of the pharmaceutical combination of the present application.

[0166] The active components in the pharmaceutical combination of the present application can be formulated separately, or some or all of them can be formulated together. In one embodiment, the pharmaceutical combination of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administrations.

[0167] The active components in the pharmaceutical combination of the present application can be administered separately, or some or all of them can be administered together. The components in the pharmaceutical combination of the present application can be administered substantially non-simultaneously, or some or all of them can be administered substantially simultaneously.

[0168] The active components in the pharmaceutical combination of the present application can be administered independently of each other, or some or all of them can be administered together by various suitable routes, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the active components of the pharmaceutical combination of the present application can be administered independently of each other, or some or all of them can be administered orally or by injection, such as intravenous injection or intraperitoneal injection.

[0169] The active components in the pharmaceutical combination of the present application can be independently of each other, or some or all of them can be together suitable dosage forms, including but not limited to: tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), powders, emulsions, suspensions, solutions, dispersants and dosage forms of sustained-release preparations for oral or non-oral administration.

[0170] The active components in the pharmaceutical combination of the present application can be independently of each other, or some or all of them can be together contain pharmaceutically acceptable carriers and / or excipients.

[0171] The pharmaceutical combination of the present application can also contain additional therapeutic agents. In one embodiment, the additional therapeutic agent can be a therapeutic agent known in the art for treating hepatitis B virus infection.

[0172] In some embodiments, an effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof can be administered to an individual in need simultaneously, sequentially or at intervals.

[0173] In some embodiments, an effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof can be administered to an individual in need according to the same or different dosing regimens.

[0174] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, or once every three weeks.

[0175] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a dose of 0.1 to 10.0 mg per administration, preferably 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, 10.0 mg, or a dose within the range formed by any of the above values. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a dose of 0.2 to 5.0 mg, 0.4 to 4.0 mg, 0.5 to 3.0 mg, 0.6 to 2.6 mg, 0.8 to 2.2 mg, 0.8 to 1.8 mg, 1.0 to 2.0 mg, 1.0 to 1.8 mg, or 1.0 to 1.6 mg per administration.

[0176] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 0.2 to 5.0 mg, 0.4 to 4.0 mg, 0.5 to 3.0 mg, 0.6 to 2.6 mg, 0.8 to 2.2 mg, 0.8 to 1.8 mg, 1.0 to 2.0 mg, 1.0 to 1.8 mg, or 1.0 to 1.6 mg per administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 1.0 to 1.8 mg per administration.

[0177] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, or once every three weeks.

[0178] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof is administered at a dose of 0.005 mg to 5.0 mg per administration, preferably 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg or a dose within the range formed by any of the above values. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof is administered at a dose of 0.05 mg to 5.0 mg, 0.10 mg to 2.0 mg, 0.25 mg to 2.0 mg, 0.5 mg to 1.0 mg per administration.

[0179] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof is administered once a day at a dose of 0.10 mg to 2.0 mg per administration. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof can be administered once a day at a dose of 0.5 mg per administration.

[0180] In some embodiments, the TLR7 agonist (i.e., the compound of Formula I) is administered once a week at a dose of 1.0 - 1.8 mg per administration; entecavir is administered once a day at a dose of 0.5 mg per administration.

[0181] Technical effects

[0182] The drug combination of the present application can significantly reduce the HBV DNA level or alleviate other HBV indicators; and compared with single drugs, the drug combination of the present application shows a significant enhancement effect. This indicates that the drug combination of the present application has good medicinal value.

[0183] Description of the Drawings

[0184] Figure 1 Effect of TLR7 agonist on the level of HBV DNA replication in the serum of AAV mice. Detailed Description of the Invention

[0185] For clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0186] Example 1 AAV mouse test

[0187] 1.1 Test Drugs

[0188] In this example, the TLR7 agonist is (2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine), and the preparation method can be referred to WO2016023511.

[0189] In this example, the entecavir used is its monohydrate.

[0190] 1.2 Test Methods and Grouping

[0191] Male C57BL / 6 mice (Shanghai SLAC Laboratory Animal Co., Ltd.) at 6 - 8 weeks of age were taken and, according to 1×10 11The vg dose of rAAV8-1.3HBV virus (Beijing WuJiaHe Institute of Molecular Medicine) was injected into C57BL / 6 mice via the tail vein. At the 2nd and 4th weeks after virus injection, blood was collected from the orbital cavity of the mice, serum was separated, and the copy number of HBV-DNA in the serum was measured to determine whether the model was successfully constructed. The mice were randomly grouped according to the copy number of HBV DNA, and a solvent control group, a TLR7 agonist group (20 mg / kg, tiw), an entecavir (ETV) group (0.0032 (1st week, 1W) & 0.001 (2nd - 6th weeks, 2 - 6W) mg / kg, qd), and a combination group of TLR7 agonist and ETV were set up, with 6 mice in each group. Each group of mice was continuously administered for 6 weeks by gavage and then withdrawn for 3 weeks. During the administration period, blood was collected from the orbital cavity at the 1st, 2nd, 3rd, 4th, 5th, 6th weeks and 1st, 2nd, 3rd weeks after drug withdrawal, serum was separated, and the copy number of HBV DNA in the serum was detected by fluorescence quantitative PCR method.

[0192] Group:

[0193] i. Solvent control group;

[0194] ii. Monotherapy group: Entecavir group;

[0195] iii. Monotherapy group: TLR7 agonist group;

[0196] iv. Combination group (combo): TLR7 agonist and entecavir;

[0197] Table 1-1. Drug administration plan

[0198]

[0199] Note: i.g.: Gavage; qd: Administer once a day; tiw: Administer once every three days; 6w: Six weeks. The drug administration method of the combination group is the same as that of the monotherapy group.

[0200] 1.3 Method for evaluating drug combination

[0201] The Jin Zhengjun method was used to evaluate the results of this experiment. The Jin Zhengjun method is a method obtained by analyzing the disadvantages of the Burgi formula method and making corrections on this basis, and is also called the probability addition method:

[0202] The combined effect was calculated according to the following formula: q = E A+B / (E A +E B –E A ×E B )

[0203] Among them, E A represents the effect of drug A administered alone; E B represents the effect of drug B administered alone; EA+B Represents the effect after the combined administration of Drugs A and B.

[0204] The meaning of the q value: 0.85 - 1.15 represents simple addition; greater than 1.15 - 20 represents potentiation; greater than 20 represents significant increase; less than 0.85 - 0.55 represents antagonism; less than 0.55 represents significant antagonism. The absolute value of the q value is taken.

[0205] 1.4 Results

[0206] The results are shown in Table 1 - 2, Table 1 - 3, Table 1 - 4 and Figure 1 .

[0207] Table 1 - 2. Effects of different therapies on the replication level of HBV DNA (log 10 IU / mL) in mouse serum (treatment stage)

[0208]

[0209] Note: Compared with the vehicle control group, *P < 0.05, **P < 0.01, ***P < 0.001.

[0210] Table 1 - 3. Effects of different therapies on the replication level of HBV DNA (log 10 IU / mL) in mouse serum (post - drug - withdrawal stage)

[0211]

[0212] Note: Compared with the vehicle control group, *P < 0.05, **P < 0.01, ***P < 0.001.

[0213] Table 1 - 4. Results of the Jin Zhengjun method evaluation of combined drug use

[0214]

[0215] During the 42 - day treatment period, the HBV DNA in mice in the monotherapy groups of entecavir and TLR7 agonist (Group ii and Group iii) decreased significantly, and the HBV DNA in the combination group (Group iv) decreased significantly. The q - value results showed that the combined drug use exhibited excellent synergistic effects.

[0216] Example 2

[0217] 1. Test drugs

[0218] In this example, the TLR7 agonist is (2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine), the preparation method can be referred to WO2016023511. Prepare it into tablets with specifications of 0.2mg / tablet or 0.5mg / tablet for standby.

[0219] Entecavir: Commercially available entecavir tablets, with a specification of 0.5mg / tablet. Commercially available entecavir tablets include but are not limited to entecavir dispersible tablets (Runzhong ).

[0220] Placebo: Placebo of TLR7 agonist.

[0221] 2. Enrolled subjects

[0222] All of the following criteria need to be met:

[0223] 1) Male patients aged 18 - 65 (inclusive) and female patients who are not pregnant and not lactating.

[0224] 2) Serum virological criteria: Serum HBsAg is positive for more than 6 months or there is evidence of chronic hepatitis B for 6 months.

[0225] 3) Treated patients: The medical history record shows that HBV DNA suppression was < the lower limit of normal detection 24 weeks before enrollment. Using Roche reagents for detection during the screening period, HBV DNA suppression is defined as < 69 IU / mL; Fibroscan ≤ 9.0 Kpa (fasting), ALT ≤ 5 × ULN.

[0226] 4) Naive patients: Chronic hepatitis B patients with positive HBeAg, HBV DNA > 10 5 copies / mL (or > 20000 IU / mL), or for patients with negative HBeAg, HBV DNA > 10 4 copies / mL (or > 2000 IU / mL), detected by Roche second-generation Cobas Taqman real-time quantitative PCR method, with a lower limit of detection of 20 IU / mL; Fibroscan ≤ 12.4 Kpa (fasting), 1 × ULN ≤ ALT ≤ 5 × ULN. The naive patients refer to those who have never received HBV antiviral drugs or participated in relevant clinical trials.

[0227] 3. Dosage

[0228] TLR7 agonist: Administered once a week.

[0229] Entecavir: The administered dose is 0.5mg / day, once a day.

[0230] The first group consisted of 12 subjects, among whom 8 took 1.2 mg TLR7 agonist combined with entecavir, and 4 took placebo combined with entecavir, and they took medicine for 24 weeks in total.

[0231] The second, third, and fourth groups each had 36 subjects, and they were randomly assigned in the ratio of TLR7 agonist: placebo = 5:1. They respectively received 1.0 mg TLR7 agonist combined with entecavir or placebo combined with entecavir (the second group), 1.5 mg TLR7 agonist combined with entecavir or placebo combined with entecavir (the third group), 1.8 mg TLR7 agonist combined with entecavir or placebo combined with entecavir (the fourth group). Each dose group took medicine for 24 weeks in total.

[0232] 4. Efficacy indicators

[0233] Efficacy indicators: Serum HBsAg, HBeAg, or HBV DNA, etc.

[0234] Exploratory indicators: HBV RNA and HBcrAg, etc.

[0235] The average content of the index parameters at each detection time point in each group and the change value compared with the baseline were described using mean, standard deviation, median, quartiles, minimum value, and maximum value; the repeated measurement mixed effects model (MMRM) was used, with group, baseline value, detection time point, and the interaction term of group and detection time point as fixed effects, and subjects and intercept term as random effects. The change values of the index parameters at each detection time point in each group relative to the baseline were respectively compared with the placebo group, and Dunnett's method was used for correction.

[0236] 5. Results

[0237] All groups with TLR7 agonist combined with entecavir significantly inhibited HBV DNA replication in patients. The combined administration group of TLR7 agonist and placebo achieved inhibition of HBV DNA replication. The combined administration group of entecavir and placebo also had an inhibitory effect on HBV DNA replication.

Claims

1. Use of a drug combination in the preparation of a drug for treating hepatitis B virus infection, the drug combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, monohydrate thereof, the compound of formula I or a pharmaceutically acceptable salt thereof being selected from a compound of formula A or a pharmaceutically acceptable salt thereof, 。 2. Use of a drug combination in the preparation of a drug for treating hepatitis B virus infection, the drug combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir maleate monohydrate, the compound of formula I or a pharmaceutically acceptable salt thereof being selected from a compound of formula A or a pharmaceutically acceptable salt thereof, 。 3. The use according to claim 1, characterized in that, The pharmaceutically acceptable salts of the compound of formula A are selected from maleate or fumarate.

4. The use according to claim 1, characterized in that, The compound of formula A or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the pharmaceutical composition is a pharmaceutical composition with a single dose of 0.01 mg to 10 mg.

5. The use according to claim 1, characterized in that, The pharmaceutically acceptable salt of entecavir is selected from maleate.

6. The use according to claim 5, characterized in that, The pharmaceutically acceptable salt of entecavir is selected from maleate monohydrate.

7. The use according to claim 1, wherein The entecavir or a pharmaceutically acceptable salt, monohydrate thereof is selected from entecavir maleate or entecavir monohydrate.

8. The use according to claim 1 or 2, characterized in that, The entecavir or a pharmaceutically acceptable salt, monohydrate thereof or the entecavir maleate monohydrate is in the form of a pharmaceutical composition.

9. The use according to claim 8, characterized in that, The pharmaceutical composition of the entecavir or a pharmaceutically acceptable salt, monohydrate thereof or the entecavir maleate monohydrate is selected from a pharmaceutical composition with a single dose of 0.01 mg to 5 mg.

10. The use according to claim 1 or 2, characterized in that, The ratio of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to the entecavir or a pharmaceutically acceptable salt, monohydrate thereof or the entecavir maleate monohydrate in the drug combination is selected from 10:1 to 1:

10.

11. The use according to claim 10, characterized in that, The ratio of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to the entecavir or a pharmaceutically acceptable salt, monohydrate thereof or the entecavir maleate monohydrate is selected from 1:1.5 to 1:4, 1:1.6 to 1:3.8, 1:1.8 to 1:3.8, 1:1.8 to 1:3.6 or 1:2 to 1:3.

5.

12. The use according to claim 1 or 2, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof in the drug combination is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, or once every three weeks.

13. The use according to claim 1 or 2, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof in the drug combination is administered at a dose of 0.1 to 10.0 mg each time.

14. The use according to claim 13, wherein The compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 0.2 to 5.0 mg, 0.4 to 4.0 mg, 0.5 to 3.0 mg, 0.6 to 2.6 mg, 0.8 to 2.2 mg, 0.8 to 1.8 mg, 1.0 to 2.0 mg, 1.0 to 1.8 mg, or 1.0 to 1.6 mg each time.

15. The use according to claim 1 or 2, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 0.2 to 5.0 mg, 0.4 to 4.0 mg, 0.5 to 3.0 mg, 0.6 to 2.6 mg, 0.8 to 2.2 mg, 0.8 to 1.8 mg, 1.0 to 2.0 mg, 1.0 to 1.8 mg, or 1.0 to 1.6 mg per administration.

16. The use according to claim 15, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 1.0 to 1.8 mg per administration.

17. The use according to claim 1 or 2, characterized in that, The entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate of the pharmaceutical combination is administered three times a day, twice a day, once a day, or once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, or once every three weeks.

18. The use according to claim 1 or 2, characterized in that, The entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate of the pharmaceutical combination is administered at a dose of 0.005 mg to 5.0 mg per administration.

19. The use according to claim 18, characterized in that, The entecavir or a pharmaceutically acceptable salt, monohydrate thereof is administered at a dose of 0.05 mg to 5.0 mg, 0.10 mg to 2.0 mg, 0.25 mg to 2.0 mg, or 0.5 mg to 1.0 mg per administration.

20. The use according to claim 1 or 2, characterized in that, The entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate of the pharmaceutical combination is administered once a day at a dose of 0.10 mg to 2.0 mg per administration.

21. The use according to claim 20, characterized in that, The entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate of the pharmaceutical combination is administered once a day at a dose of 0.5 mg per administration.

22. The use according to claim 1 or 2, characterized in that, The pharmaceutical combination is a fixed combination.

23. The use according to claim 22, characterized in that, The fixed combination is in the form of a solid pharmaceutical composition.

24. The use according to claim 22, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate in the fixed combination are present in the same solid pharmaceutical composition.

25. The use according to claim 1 or 2, characterized in that, The pharmaceutical combination is a non-fixed combination.

26. The use according to claim 25, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, monohydrate thereof in the non-fixed combination are each in the form of a solid pharmaceutical composition.

27. The use according to claim 25, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate in the non-fixed combination are each in the form of a solid pharmaceutical composition, and the solid pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof and the solid pharmaceutical composition of entecavir or a pharmaceutically acceptable salt, monohydrate, or the entecavir monomaleate monohydrate are present in the same medicine bag.

28. The use according to claim 25, characterized in that, The compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate in the non-fixed combination are each in the form of a solid pharmaceutical composition, and the solid pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof and the solid pharmaceutical composition of entecavir or a pharmaceutically acceptable salt, monohydrate thereof, or the entecavir monomaleate monohydrate are not present in the same sachet.

29. The use according to claim 23, wherein, The solid pharmaceutical composition is selected from tablets or capsules.

30. The use according to claim 26, characterized in that, The solid pharmaceutical composition is selected from tablets or capsules.

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