Drug combinations containing TLR7 agonists

Abstract

A drug combination containing a TLR7 agonist, specifically, the compound of formula I as a TLR7 agonist in combination with entecavir for the treatment of hepatitis B virus infection, and its use, which has excellent anti-hepatitis B virus infection effects. [Formula 1] TIFF2022550387000022.tif5381

Description

[Technical Field]

[0001] This application is in the field of medicinal chemistry and relates to a drug combination comprising a TLR7 agonist, particularly to the drug combination and use of the compound of formula I as a TLR7 agonist in combination with entecavir to treat hepatitis B virus infection. As used herein, "treating hepatitis B virus infection" means "treating hepatitis B virus infection." [Background technology]

[0002] According to the World Health Organization, approximately 257 million people worldwide are infected with the hepatitis B virus (HBV). If untreated, hepatitis patients can suffer from long-term, fatal diseases such as liver failure, cirrhosis, and liver cancer.

[0003] Two common drugs currently approved for the treatment of chronic hepatitis B include nucleoside (nucleotide) compounds and interferons. Nucleoside (nucleotide) drugs, such as entecavir, can inhibit the replication of HBV DNA.

[0004] Toll-like receptors (TLRs) are expressed in various immune cells. They recognize highly conserved structural motifs, such as pathogen-associated molecular patterns (PAMPs) expressed by microbial pathogens and damage-associated molecular patterns (DAMPs) released by necrotic cells. PAMPs or DAMPs stimulate Toll-like receptors, triggering a signal cascade that activates transcription factors such as AP-1, NF-κB, and interferon regulatory factors (impulse response functions). This triggers various cellular responses, including the production of interferons, proinflammatory cytokines, and effector cytokines, resulting in an immune response. To date, 13 Toll-like receptors have been discovered in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are primarily expressed on the cell surface, while Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different Toll-like receptors recognize different pathogen-derived ligands. Toll-like receptor 7 (TLR7) is primarily expressed by plasmacytoid dendritic cells (pDCs) and induces the secretion of interferon-α (IFN-α) upon recognition by ligands. Several TLR7 agonists, such as imiquimod, resiquimod, and GS-9620, have been reported. International Publication Nos. WO2016023511 and WO2017076346 (the entire contents of which are incorporated herein by reference) disclose novel TLR7 agonists, which exhibit excellent biological activity and selectivity.

[0005] Although many options exist for treating patients infected with hepatitis B virus, there remains a need for more effective therapeutic agents for clinical use. Summary of the Invention

[0006] In one aspect, 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 or solvate thereof.

[0007] In another aspect, the present application further provides a use of the drug combination of the present application for the manufacture of a medicament for treating Hepatitis B virus infection. The present application further provides a method for treating Hepatitis B virus infection, comprising administering to an individual in need thereof an effective amount of the drug combination of the present application. The present application further provides a drug combination according to the present application for treating hepatitis B virus infection. The present application further provides a drug combination according to the present application for treating hepatitis B virus infection.

[0008] In one aspect, 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 or solvate thereof, wherein the compound of formula I is:

[0009] [ka] wherein L1 is selected from -O-; L2 is selected from -CH2-, wherein said -CH2- is optionally substituted by R4; R1 is hydrogen or C 1-10 alkyl groups, 1-10 The alkyl group is optionally substituted by R5; R2 is selected from hydrogen, a cyano group, -COOH, or -CONH2, wherein -COOH and -CONH2 are optionally substituted by R6; B is selected from a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; L3 is C 0-6 an alkylene group, or an imino group; 0-6 The alkylene group and the imino group are optionally substituted by R7; R3 is hydrogen, amino group, C 1-10 Alkyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic hydrocarbon group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, and 1-10 Alkyl group, C 3-10the cyclic hydrocarbon group, the 3-10 membered heterocyclic hydrocarbon group, the 6-10 membered aryl group, or the 5-10 membered heteroaryl group is optionally substituted by R8; or R3 and L3 together with adjacent atoms on ring B form a saturated or unsaturated 5-8 membered ring, said 5-8 membered ring optionally substituted by R9; n is 0, 1, 2, 3, 4 or 5; R4, R5, R6, R7, R8, and R9 are each independently selected from halogen, cyano, hydroxy, mercapto, amino, -R, -OR, =O, -SR, -NHR, and -NR2; R is independently C 1-8 Alkyl group, C 3-8 It is selected from a cyclic hydrocarbon group, a 3- to 8-membered heterocyclic hydrocarbon group, a 6- to 8-membered aryl group, and a 5- to 8-membered heteroaryl group.

[0010] In some embodiments of the compound of Formula I, L2 is selected from -CH2-.

[0011] In some embodiments of the compound of Formula I, R is C 1-6 alkyl groups, 1-6 The alkyl group is optionally substituted with one or more R5 groups.

[0012] In some embodiments of the compound of Formula I, R2 is selected from hydrogen, a cyano group, or -CONH2, wherein said -CONH2 is optionally substituted with one or more R6.

[0013] In some embodiments of the compound of Formula I, B is selected from a 6- to 7-membered aryl group or a 5- to 7-membered heteroaryl group. In some embodiments of the compound of Formula I, B is selected from a phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a thienyl group, a thiazolyl group, a furyl group, an oxazolyl group, a thiadiazolyl group, an isoxazolyl group, an oxadiazolyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an isothiazolyl group, or a triazolyl group. In some embodiments of the compound of Formula I, B is selected from a phenyl group, a pyridyl group, or a thiazolyl group.

[0014] In some embodiments of the compound of Formula I, L3 is C 0-6 alkylene groups, 0-6 The alkylene group is optionally substituted by one or more R7.

[0015] In some embodiments of the compound of Formula I, R3 is hydrogen, an amino group, C 1-6 Alkyl group, C 3-8 a cyclic hydrocarbon group, a 3- to 8-membered heterocyclic hydrocarbon group, a 6- to 8-membered aryl group, or a 5- to 8-membered heteroaryl group, and 1-6 Alkyl group, C 3-8 The cyclic hydrocarbon group, the 3-8 membered heterocyclic hydrocarbon group, the 6-8 membered aryl group, or the 5-8 membered heteroaryl group is optionally substituted by one or more R8, or R3, L3 and adjacent atoms on the B ring form a saturated or unsaturated 5-8 membered ring, which is optionally substituted by one or more R9. In some embodiments of the compound of Formula I, R3 is hydrogen, an amino group, C 1-6 alkyl group, piperazinyl group, morpholinyl group, tetrahydropyrrolyl group, piperidinyl group, azetidinyl group, diazepanyl group, or 2-oxa-5-azabicyclo[2.2.1]heptyl group, 1-6 The alkyl group, piperazinyl group, morpholinyl group, tetrahydropyrrolyl group, piperidinyl group, azetidinyl group, diazepanyl group, or 2-oxa-5-azabicyclo[2.2.1]heptyl group is optionally substituted by one or more R8, or R3, L3 together with adjacent atoms on ring B form a saturated or unsaturated 6-membered ring, which is optionally substituted by one or more R9.

[0016] 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.

[0017] In some embodiments of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof is 2-butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 7-(3-(aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((3,3-difluoropyrrolidin-1-yl)methyl)benzyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((3-fluoropyrrolidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)benzyl)pyrrolidin-3-ol, 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((dimethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((diethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((dipropylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 7-(4-(azetidin-1-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((3-methoxyazetidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((2,6-dimethylmorpholinyl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 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, 2-butoxy-7-(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-((4-isopropylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(3-(2-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-(1-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one, 7-benzyl-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-(2-methoxyethoxy)-7-((6-methylpyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 7-((5-chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-(2-methoxyethoxy-)-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 1-(4-((4-amino-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one, 2-butoxy-7-((5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 4-amino-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridine- 3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile, 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile, 4-amino-2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile, 4-amino-2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile, 4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide, 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, 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.

[0018] 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.

[0019] 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 0.5-2hydrate. In some embodiments, the entecavir hydrate is selected from entecavir monohydrate.

[0020] In some embodiments of the present application, the pharmaceutically acceptable salt of entecavir is selected from the maleate salt. In some embodiments of the present application, the pharmaceutically acceptable salt of entecavir is selected from the monomaleate salt.

[0021] In some embodiments of the present application, the entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.

[0022] In some embodiments of the present application, the drug combination is 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 thereof. In some embodiments, the drug combination described herein comprises 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, or its maleate or trifluoroacetate salt, and entecavir or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the drug combination described herein comprises 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine and entecavir or its monohydrate.

[0023] 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 herein comprises 2-butoxy-7-((2-(pyrrolidin-1-ylmethyl)thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine and entecavir monomaleate monohydrate.

[0024] In some embodiments of the present application, the compound of Formula I or a pharmaceutically acceptable salt thereof of the drug combination is administered once a day, twice a day, once every two days, once every three days, once every four days, or once every five days, each time at a dose of 0.0001-20 mg / kg weight (calculated by the weight of the compound of Formula I).

[0025] In some embodiments of the present application, entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is administered once a day, twice a day, or once every two days, each time at a dose of 0.5 mg or 1.0 mg (calculated by weight of entecavir).

[0026] 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 0.005-10.0 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 0.05-5.0 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 0.10-2.0 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 0.25-2.0 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 0.5-1.0 mg.

[0027] In some embodiments of the present application, the ratio (by weight) of the average daily doses of the compound of Formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination is selected from the range of 10:1 to 1:10. In some embodiments, the ratio (by weight) of the average daily doses of the compound of Formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from the range of 10:1 to 1:10. :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, The ratio may be selected from the group consisting of 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 optionally a range formed by the foregoing ratios. In some embodiments, the ratio (by weight) of the average daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt or solvate thereof is preferably selected from 1:1.5-1:4, 1:1.6-1:3.8, 1:1.8-1:3.8, 1:1.8-1:3.6, or 1:2-1:3.5.

[0028] In some embodiments of the present application, the drug combination is a defined combination. In some embodiments, the defined combination is in the form of a solid pharmaceutical composition. In some embodiments, in the defined combination, the compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof are present in the same solid pharmaceutical composition.

[0029] In some embodiments of the present application, the drug combination is an indefinite combination. In some embodiments, in the indefinite combination, the compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof are each in the form of a solid pharmaceutical composition. In some embodiments, in the indefinite combination, the compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof 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 pouch. In some embodiments, in the indefinite combination, the compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof 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 pouch.

[0030] In some embodiments of the present application, the solid pharmaceutical composition is selected from a tablet or a capsule.

[0031] In another aspect, the present application further provides the use of a drug combination according to the present application for the manufacture of a medicament for treating Hepatitis B virus infection, wherein the drug combination is as described above.

[0032] In another aspect, the present application further provides a method for treating hepatitis B virus infection, comprising administering to an individual in need thereof an effective amount of a drug combination according to the present application, wherein the drug combination is as described above.

[0033] In another aspect, the present application further provides a drug combination according to the present application for treating Hepatitis B virus infection, said drug combination being as described above.

[0034] In another aspect, the present application further provides the use of a drug combination according to the present application for treating Hepatitis B virus infection, said drug combination being as described above.

[0035] In some embodiments, the present application provides a use of a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising entecavir or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating hepatitis B virus infection, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is The salts thereof and entecavir or pharmaceutically acceptable salts thereof, solvates thereof are each prepared as pharmaceutical compositions.

[0036] In some embodiments, the present application further provides a kit for treating hepatitis B virus infection, comprising: (a) a first pharmaceutical composition comprising, as an active ingredient, the compound of Formula I or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition comprising, as an active ingredient, entecavir or a solvate thereof, and optionally (c) instructions for coadministering the compound of Formula I or a pharmaceutically acceptable salt thereof with entecavir or a pharmaceutically acceptable salt or solvate thereof.

[0037] "Compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof" In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from a compound of Formula A or a pharmaceutically acceptable salt thereof.

[0038] [ka]

[0039] The compound of formula A is a 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 found in WO2016023511.

[0040] In some embodiments, the pharmaceutically acceptable salt of the compound of formula A is selected from a maleate or a fumarate salt.

[0041] In some embodiments, the pharmaceutical composition of the Formula A compound or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, preferably selected from tablets or capsules.

[0042] 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 having a single dose of 0.01-10 mg, preferably 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 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 .0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2. 4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2m g, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg , 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9 The pharmaceutical composition is selected from pharmaceutical compositions containing a single dose of 0.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, 10.0 mg, or any range formed by any of the above values.

[0043] "Entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutical composition thereof" In this 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 has the following structural formula: [ka]

[0044] In some embodiments, the entecavir includes a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the maleate salt. In some embodiments, the entecavir pharmaceutically acceptable salt is selected from the monomaleate salt.

[0045] In some embodiments, the entecavir includes a solvate thereof, and the solvate is selected from an entecavir hydrate. In some embodiments, the entecavir hydrate is selected from an entecavir 0.5-2hydrate. In some embodiments, the entecavir hydrate is selected from an entecavir monohydrate.

[0046] In some embodiments, the entecavir is selected from entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.

[0047] In some embodiments, entecavir or a pharmaceutically acceptable salt or solvate thereof is in the form of a pharmaceutical composition. Preferably, the pharmaceutical composition is selected from solid pharmaceutical compositions. Preferably, the solid pharmaceutical composition is selected from tablets or capsules.

[0048] In some embodiments, the pharmaceutical composition of entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from pharmaceutical compositions containing a single dose of 0.01-5 mg, preferably 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 g, 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 range formed by any of the above values.

[0049] In the present application, said entecavir or a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutical composition thereof may be selected from commercially available products.

[0050] "Definitions and Explanations" Unless otherwise specified, the following terms used in this application have the meanings set forth below. Certain terms are to be understood in their ordinary sense in the art, rather than being left open or unclear, unless otherwise defined.

[0051] As used herein, the compounds of Formula I or pharmaceutically acceptable salts thereof are TLR7 agonists.

[0052] In this 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 has the following structural formula: [ka]

[0053] In this application, the structural formulas and chemical names of some compounds according to the formula I or pharmaceutically acceptable salts thereof are as follows: [ka] TIFF0007749545000006.tif222160TIFF0007749545000007.tif232160TIFF0007749545 000008.tif216160TIFF0007749545000009.tif228161TIFF0007749545000010.tif95160

[0054] In the present application, the compounds of formula I include their non-salt forms (e.g., free acids or free bases) as well as their pharmaceutically acceptable salts, both of which are included in the scope of protection of the present application. For example, pharmaceutically acceptable salts of the compounds of formula I include hydrochloride, maleate, or fumarate.

[0055] In the present application, the entecavir includes both its unsolvated form and its solvated form, and both the unsolvated and solvated forms are included in the scope of protection of the present application.When a solvated form is selected, the ratio of the amount of substance of the compound to the solvent is selected from 1:0.5, 1:1, 1:1.5, 1:2, or any range formed by any endpoint, for example, 1:0.5-1:2, 1:0.5-1:1.5, or 1:1-1:1.5.For example, the entecavir is in a nonsolvated form.For example, the entecavir is in a hydrate form.For example, the entecavir is in a monohydrate form.

[0056] In this application, the dose is calculated by weight of the free form of the compound, which refers to the non-salt compound and the non-solvate form.

[0057] The term "substituted" or "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the resulting compound is stable. When the substituent is oxo (=O), two hydrogen atoms are replaced. Oxygen substitution does not occur on aryl groups.

[0058] The term "optionally" or similar expressions means that the subsequently described event or circumstance may or may not occur, and includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, when an ethyl group is "optionally" substituted with a halogen, the ethyl group may be unsubstituted (-CHCH), monosubstituted (e.g., -CHCHF), multiply substituted (e.g., -CHFCHF, -CHCHF, etc.), or fully substituted (e.g., -CFCF). As will be understood by those skilled in the art, groups containing one or more substituents do not permit substitution or forms of substitution that are spatially incompatible and / or synthetically impossible.

[0059] As used herein, "C m-n " means that the moiety has an integer number of carbon atoms in the specified range. For example, "C 1-6 means that the group in question has 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0060] When a particular variable (e.g., R) occurs more than once in a compound composition or structure, each occurrence is independently defined. Thus, for example, if a functional group is substituted with two R, each R is independently selected.

[0061] When the number of a particular connecting group is 0, for example, -(CH2)0-, this indicates that the connecting group is a covalent bond.

[0062] When a bond of a substituent crosses two atoms of a ring, the substituent can be bonded to any atom of the ring. For example, the structural unit [ka] or [ka] can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0063] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0064] The term "hydroxy" refers to an --OH group.

[0065] The term "cyano" refers to the group -CN.

[0066] The term "mercapto" refers to -SH.

[0067] The term "amino group" refers to the -NH2 group.

[0068] The term "alkyl group" refers to a C n H 2n+1 The term "C" refers to a hydrocarbon group having the general formula: 1-6 "Alkyl" refers to an alkyl group containing 1-6 carbon atoms (e.g., 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, this definition applies to the alkyl (i.e., -alkyl) portions of alkoxy, monoalkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups.

[0069] The term "alkoxy" refers to an --O-alkyl group.

[0070] The term "cycloalkyl group" refers to a fully saturated carbocyclic ring that exists as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, such carbocyclic rings generally have 3-10 members. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, and the like.

[0071] The term "cyclic hydrocarbon group" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing one or two rings. The cyclic hydrocarbon group may be a monocyclic, fused polycyclic, bridged, or spirocyclic structure. Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like.

[0072] The term "heterocyclyl group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaryl groups) and exists as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, such heterocyclic rings are generally 3-7 membered rings containing 1-3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

[0073] The term "heterocycloalkyl group" refers to a fully saturated cyclic group that exists as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycle generally is a 3- to 7-membered ring containing 1-3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups. Examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydrofuryl. Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups, and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.

[0074] The term "heterocyclic hydrocarbon group" refers to a non-aromatic cyclic group, whether monocyclic, fused polycyclic, bridged, or spirocyclic, some of whose ring atoms are N, O, S(O), n(n is 0, 1, or 2), and the remaining ring atoms are C. Such rings may be saturated or unsaturated (e.g., have one or more double bonds), but do not have a completely conjugated π-electron system. Examples of 3-membered heterocyclic hydrocarbon groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups; examples of 4-membered heterocyclic hydrocarbon groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; and examples of 5-membered heterocyclic hydrocarbon groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuryl, and dihydrothienyl. Examples of 6-membered heterocyclic hydrocarbon groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,2-, 1,4-dithianyl, dihydropyridyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyranyl, and dihydrothiopyranyl groups, and examples of 7-membered heterocyclic hydrocarbon groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and oxazabicyclo[2.2.1]heptyl groups. , azaspiro[3.3]heptyl groups, and the like.

[0075] The term "aryl group" refers to an aromatic cyclic group having an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene, and the like.

[0076] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system having at least one ring atom selected from N, O, or S, the remaining ring atoms being C, and at least one aromatic ring. Heteroaryl groups preferably have a single 5-8 membered ring or multiple fused rings containing 6-14, especially 6-10, ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, and the like.

[0077] The compounds of the present application may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise specified, all stereoisomers, including enantiomers and diastereomers, are included. Compounds containing asymmetric carbon atoms of the present application can be isolated in optically pure or racemic form. Optically pure forms can be separated from racemic mixtures or synthesized using asymmetric starting materials or reagents.

[0078] The term "administering" means physically introducing a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0079] The term "treatment" generally refers to achieving a desired pharmacological and / or physiological effect. Such effect is therapeutic if it partially or completely stabilizes or cures a disease and / or its associated side effects. As used herein, the term "treatment" includes any treatment of a patient's disease, either (a) inhibiting the symptoms of the disease, i.e., preventing its progression, or (b) ameliorating the symptoms of the disease, i.e., eliminating the disease or symptoms.

[0080] The term "effective amount" refers to the amount of a compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, improves, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The "therapeutically effective amount" of a compound of the present application is determined based on the compound itself, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, and can be determined by one of ordinary skill in the art based on their knowledge and the contents of this disclosure.

[0081] The term "individual" may be a mammal. In some embodiments, the subject is a mouse. In some embodiments, the subject is a human.

[0082] In the present application, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered by any suitable route and method, for example, orally or parenterally (e.g., intravenously). A therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 0.0001-20 mg / kg body weight / day, including, but not limited to, about 0.001-10 mg / kg body weight / day. The dose and frequency of administration of the compound of Formula I or a pharmaceutically acceptable salt thereof will be determined by the needs of the individual patient, including the severity, response of the disease, treatment-related toxicities, and the patient's age and health condition, for example. For example, once or twice daily, or three or more times daily. Administration can be intermittent, for example, administering a daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof to a subject over a period of several days, followed by several days or a longer period in which the patient does not receive a daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0083] Entecavir can be administered by various routes, including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal. In certain embodiments, it is administered orally. The dosage of entecavir can be determined based on the severity of the disease, disease response, treatment-related toxicity, and the patient's age or health status. For example, the daily dose of entecavir is 0.005-10.0 mg. Entecavir can be administered once or multiple times daily. In some embodiments, an oral solid formulation of entecavir is administered once daily.

[0084] The term "about" is understood to include up to three standard deviations from the mean, or up to the standard tolerance in a particular field. In some embodiments, "about" is understood to mean a difference of not more than 0.5. "About" modifies the value that follows it. For example, "about 1, 2, 3" means "about 1," "about 2," or "about 3."

[0085] The term "drug combination" refers to the simultaneous, concurrent or sequential use of two or more active ingredients in combination.

[0086] The term "defined combination" refers to the administration of the active ingredients (e.g., TLR7 agonist or entecavir) to a subject simultaneously in a defined total dose or dose ratio, or in the form of a single entity, pharmaceutical composition, or formulation, which in some embodiments is present in, for example, the same tablet, or the same capsule, or the same sachet.

[0087] The term "indefinite combination" refers to the administration of two or more active ingredients as separate entities (e.g., pharmaceutical compositions, formulations) simultaneously, concurrently, or sequentially, without any particular time limit, to an individual, where the active ingredients administered to the individual reach a therapeutically effective dose level. An example of an indefinite combination is cocktail therapy, where, for example, two, three, or more active ingredients are administered. In an indefinite combination, the active ingredients can be packaged, sold, or administered as completely separate pharmaceutical compositions. The "indefinite combination" includes multiple "definite combinations," or a "definite combination" combined with any one or more separate active ingredients.

[0088] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their drug combinations or salts thereof with pharmaceutically acceptable excipients. A pharmaceutical composition facilitates administration of a compound of the present application or its drug combination to a subject.

[0089] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, are not toxic or irritating, and are not likely to cause an allergic reaction or other problem or complication, and for which the benefit-risk ratio is reasonable.

[0090] The term "pharmaceutically acceptable salts" or similar expressions refers to salts of compounds of the present application that fall within the definition of "pharmaceutically acceptable."

[0091] Unless otherwise specified, the singular covers the plural and the plural covers the singular. Unless otherwise specified, the terms "one" or "one" means "at least one." Unless otherwise specified, "or" means "and / or."

[0092] In this specification, unless otherwise stated, the term "comprises" or equivalent terms are used in an open manner and mean that the invention may include unspecified elements, components, or steps in addition to the listed elements, components, or steps.

[0093] Any patents, patent applications, or existing publications are incorporated herein for purposes of illustration and disclosure. These publications are provided because they were published prior to the filing date of the present application. Any statement as to the disclosure date of any such document or representation of its contents is based on the information known to the applicant and does not constitute an admission as to the accuracy of the disclosure date of such document or of the contents thereof. Furthermore, the incorporation of any such publication by reference does not constitute an admission that such publication constitutes common general knowledge in the art in any country.

[0094] "Administration method" The following does not limit the administration method of the drug combination according to the present application.

[0095] The active ingredients of the pharmaceutical combinations of the present application may be formulated individually, or some or all of them may be formulated together. In one embodiment, the pharmaceutical combinations of the present application may be prepared as pharmaceutical compositions suitable for single or multiple administration.

[0096] The active ingredients of the pharmaceutical combinations of the present application may be administered singly, or some or all of them may be administered simultaneously. The active ingredients of the pharmaceutical combinations of the present application may be administered substantially non-concurrently, or some or all of them may be administered substantially simultaneously.

[0097] The active ingredients of the pharmaceutical combinations described herein can be administered individually or in part or in whole simultaneously by any suitable route, including, but not limited to, oral, parenteral (intravenous, intramuscular, topical, or subcutaneous), hi some embodiments, the active ingredients of the pharmaceutical combinations described herein can be administered individually or in part or in whole simultaneously by oral or injection, for example, intravenous or intraperitoneal injection.

[0098] The active ingredients of the pharmaceutical combinations of the present application may each be independently, or some or all of them together, may be in any suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injectables (intramuscular, intravenous, intraperitoneal), powders, emulsions, suspensions, solutions, dispersions, and sustained-release formulations for oral or parenteral administration.

[0099] The active ingredients of the pharmaceutical combinations of the present application may each independently, or some or all of them together, comprise pharmaceutically acceptable carriers and / or excipients.

[0100] The drug combinations of the present application may further comprise other therapeutic agents, which in one embodiment may be any therapeutic agent known in the art for treating Hepatitis B virus infection.

[0101] In some embodiments, an individual in need thereof can be administered effective amounts of a compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof simultaneously, sequentially, or at an interval.

[0102] 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 or solvate thereof can be administered to an individual in need thereof in the same or different dosing regimens.

[0103] 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.

[0104] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in a dose of 0.1-10.0 mg each time, 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 g, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg , 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4 .8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6. 2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6m g, 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 any value within a range formed therein. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 0.2-5.0 mg, 0.4-4.0 mg, 0.5-3.0 mg, 0.6-2.6 mg, 0.8-2.2 mg, 0.8-1.8 mg, 1.0-2.0 mg, 1.0-1.8 mg, or 1.0-1.6 mg each time.

[0105] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 0.2-5.0 mg, 0.4-4.0 mg, 0.5-3.0 mg, 0.6-2.6 mg, 0.8-2.2 mg, 0.8-1.8 mg, 1.0-2.0 mg, 1.0-1.8 mg, or 1.0-1.6 mg. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once a week at a dose of 1.0-1.8 mg.

[0106] In some embodiments, the entecavir or a pharmaceutically acceptable salt or 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.

[0107] In some embodiments, the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of 0.005-5.0 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 , 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2 .7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0 In some embodiments, the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of 0.05-5.0 mg, 0.10-2.0 mg, 0.25-2.0 mg, or 0.5-1.0 mg each time.

[0108] In some embodiments, the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered once daily at a dose of 0.10-2.0 mg each time. In some embodiments, the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered once daily at a dose of 0.5 mg each time.

[0109] 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 each time, and the entecavir is administered once a day at a dose of 0.5 mg each time. [Effects of the Invention]

[0110] The drug combination of the present application can significantly reduce HBV DNA levels or improve other HBV indicators, and compared with single drugs, the drug combination of the present application shows a significant enhancing effect, indicating the high medicinal value of the drug combination of the present application. [Brief explanation of the drawings]

[0111] [Figure 1] Figure 1 shows the effect of TLR7 agonists on HBV DNA replication levels in the serum of AAV mice. DETAILED DESCRIPTION OF THE INVENTION

[0112] The present invention will now be further described with reference to examples, but the scope of the present invention is not limited to these examples. All reagents used in the present invention are commercially available products and can be used without purification.

[0113] Example 1: AAV Mouse Studies 1.1. Study Drug In this example, the TLR7 agonist is [ka] (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine), and reference WO2016023511 can be referred to for its production method.

[0114] In this example, entecavir is used as the monohydrate.

[0115] 1.2. Test method and grouping Male C57BL / 6 mice aged 6-8 weeks (Shanghai SiLaiC Laboratory Animal Co., Ltd.) were used at a dose of 1 × 10 11 rAAV8-1.3HBV virus (Beijing Wujiahe Institute of Molecular Medicine) was administered to C57BL / 6 mice via tail vein injection. Two and four weeks after virus injection, blood was collected from the orbit of the mouse, serum was separated, and the HBV DNA copy number in the serum was measured. The success of the model creation was assessed by measuring the number of HBV copies. Mice were randomly assigned to groups based on HBV DNA copy number: vehicle control, TLR7 agonist group (20 mg / kg, intravenous), entecavir (ETV) group (0.0032 mg / kg (week 1, 1 week) and 0.001 mg / kg (weeks 2-6, 2-6 weeks) qd), and TLR7 agonist and ETV combination group. Each group consisted of six mice. Mice in each group were intragastrically administered for 6 consecutive weeks followed by a 3-week washout period. Blood was collected from the orbit at weeks 1, 2, 3, 4, 5, and 6 of treatment and at weeks 1, 2, and 3 of washout. Serum was isolated and HBV DNA copy number in the serum was detected by fluorescent quantitative PCR.

[0116] group: i. Solvent control, ii. Single agent group: Entecavir group, iii. Single agent group: TLR7 agonist group, iv. Combination group (combo): TLR7 agonist and entecavir. [Table 1-1] Note: ig: intragastric administration, qd: once daily administration, tiw: once every 3 days administration, 6w: 6 weeks. The administration method in the combination group is the same as that in the monotherapy group.

[0117] 1.3. Methods for evaluating drug combinations The results of this test were evaluated using the Kim (Kim Jeong-gyun) method, which was developed by analyzing and correcting the shortcomings of the Burgi method, and is also known as the probability addition method. Formula:q=E A+B / (E A +E B -E A ×E B ) to calculate the combined effect. where E A represents the effect of drug A alone, and E B represents the effect of drug B alone, and E A+B represents the effect after administering both A and B in combination.

[0118] The meaning of the q value is as follows: 0.85 or more and 1.15 or less is the sum of simple values, more than 1.15 and 20 or less is enhancement, more than 20 is a significant increase, 0.55 or more and less than 0.85 is antagonism, and less than 0.55 is significant antagonism. The q value is an absolute value.

[0119] 1.4.Results For the results, see Tables 1-2, 1-3, 1-4 and Figure 1. [Table 1-2] Note: Compared to the vehicle control, * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001. [Table 1-3] Note: Compared to the vehicle control, * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001. [Table 1-4] During the 42-day treatment period, HBV DNA in mice was significantly reduced in the entecavir and TLR7 agonist single-drug groups (groups ii and iii), and HBV DNA was significantly reduced in the combination group (group iv), and the q value results showed that the combination administration had an excellent synergistic effect.

[0120] Example 2 1. Test drug In this example, the TLR7 agonist is [ka] (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine), and its preparation method can be found in WO2016023511. It is prepared and used in tablets of 0.2 mg / tablet or 0.5 mg / tablet.

[0121] Entecavir is available in commercially available entecavir tablets, 0.5 mg / tablet. Commercially available entecavir tablets include, but are not limited to, entecavir dispersible tablets (Junshu®).

[0122] The placebo is a fake TLR7 agonist.

[0123] 2. Inclusion criteria All of the following criteria must be met: 1) Male patients and non-pregnant, non-lactating female patients aged 18-65 (inclusive). 2) Serovirological criteria: serum HBsAg positivity persisting for more than 6 months or evidence of chronic hepatitis B for 6 months. 3) Treatment-experienced patients: 24 weeks before enrollment, medical history recorded HBV DNA inhibition < normal detection limit, HBV DNA inhibition detected by Roche HBV reagent at screening defined as < 69 IU / mL, Fibroscan ≤ 9.0 Kpa (fasting), and ALT ≤ 5 × ULN. 4) First patient: HBV DNA>10 5Patients with HBeAg-positive chronic hepatitis B with HBV DNA >10 copies / mL (or >20,000 IU / mL) 4 The patients were HBeAg negative with HBV antibody titers of ≥2000 copies / mL (or ≥2000 IU / mL), and were tested by real-time quantitative PCR using Roche's Cobas Taqman 2nd generation, with a lower detection limit of 20 IU / mL, Fibroscan <12.4 Kpa (fasting), and 1×ULN <5×ULN. The "first-time patients" referred to those who had not received anti-HBV drug treatment or participated in related clinical trials.

[0124] 3. Dosage regimen The TLR7 agonist was administered once a week. Entecavir was administered at a dose of 0.5 mg / day once daily.

[0125] Group 1 consisted of a total of 12 subjects, of whom 8 received 1.2 mg of a TLR7 agonist plus entecavir and 4 received a placebo plus entecavir combination for a total of 24 weeks.

[0126] Groups 2, 3, and 4 each consisted of 36 subjects, randomly assigned in a 5:1 ratio of TLR7 agonist to placebo. They received 1.0 mg of TLR7 agonist plus entecavir or placebo plus entecavir (Group 2), 1.5 mg of TLR7 agonist plus entecavir or placebo plus entecavir (Group 3), and 1.8 mg of TLR7 agonist plus entecavir or placebo plus entecavir (Group 4). Each dose group was administered for a total of 24 weeks.

[0127] 4.Efficacy indicators Confirmatory indicators: serum HBsAg, HBeAg, HBV DNA, etc. Indicators to consider: HBV RNA, HBcrAg, etc.

[0128] The mean content of index parameters at each detection time point in each group and the change value from baseline were explained using the mean, standard deviation, median, quartile, minimum and maximum values. A repeated measures mixed effects model (MMRM) was adopted, with the group, baseline value, detection time point, and the interaction term between group and detection time point as fixed effects, and the subject and intercept term as random effects. The change value from baseline of index parameters at each detection time point in each group was compared with the placebo group, and corrected using Dunnett's method.

[0129] 5.Results All TLR7 agonists combined with entecavir significantly inhibited HBV DNA replication in patients. The TLR7 agonist combined with placebo also inhibited HBV DNA replication. The entecavir combined with placebo also demonstrated an inhibitory effect on HBV DNA replication.

Claims

1. A drug combination for treating hepatitis B virus infection, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof, wherein said compound of formula I is a compound of formula A. 【Chemistry 1】

2. 2. The drug combination for treating hepatitis B virus infection according to claim 1, wherein the entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from entecavir maleate, entecavir monomaleate, entecavir hydrate, entecavir 0.5-2hydrate, or entecavir monohydrate, and optionally, the entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from entecavir monomaleate monohydrate.

3. 3. The drug combination for treating hepatitis B virus infection according to claim 1 or claim 2, wherein the ratio of average daily doses of the compound of Formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt, solvate thereof is selected from 10:1-1:10, optionally, the ratio of average daily doses is selected from 1:1.5-1:4, 1:1.6-1:3.8, 1:1.8-1:3.8, 1:1.8-1:3.6, or 1:2-1:3.

5.

4. The compound of Formula I or a pharmaceutically acceptable salt thereof of the drug combination is administered three times daily.

4. The drug combination for treating hepatitis B virus infection according to any one of claims 1 to 3, characterized in that it is administered 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.

5. 5. The drug combination for treating hepatitis B virus infection according to any one of claims 1 to 4, wherein the compound of formula I or a pharmaceutically acceptable salt thereof of the drug combination is administered in a dose of 0.1-10.0 mg per administration, optionally wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered in a dose of 0.2-5.0 mg, 0.4-4.0 mg, 0.5-3.0 mg, 0.6-2.6 mg, 0.8-2.2 mg, 0.8-1.8 mg, 1.0-2.0 mg, 1.0-1.8 mg, or 1.0-1.6 mg per administration.

6. 6. The drug combination for treating hepatitis B virus infection according to any one of claims 1 to 5, wherein entecavir or a pharmaceutically acceptable salt or solvate 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.

7. 7. The drug combination for treating hepatitis B virus infection according to any one of claims 1 to 6, wherein the entecavir or pharmaceutically acceptable salt or solvate thereof in the drug combination is administered at a dose of 0.005-5.0 mg per administration, and optionally the entecavir or pharmaceutically acceptable salt or solvate thereof is administered at a dose of 0.05-5.0 mg, 0.10-2.0 mg, 0.25-2.0 mg, or 0.5-1.0 mg per administration.

8. 8. A drug combination for treating hepatitis B virus infection according to any one of claims 1 to 7, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, solvate thereof in said drug combination are comprised in the same pharmaceutical composition or have the same formulation form, optionally wherein said drug combination is in the form of a solid pharmaceutical composition, and optionally wherein the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, solvate thereof in said drug combination are present in the same solid pharmaceutical composition.

9. The compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, solvate in said drug combination are each contained in separate pharmaceutical compositions or have different formulation forms, optionally the compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, solvate in said drug combination are each contained in separate solid pharmaceutical compositions, optionally the compound of Formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof, solvate in said drug combination are each contained in separate solid pharmaceutical compositions, and the compound of Formula I or a pharmaceutically acceptable salt thereof 8. A drug combination for treating hepatitis B virus infection according to any one of claims 1 to 7, wherein 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, and optionally the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the drug combination are each contained in separate solid pharmaceutical compositions, 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.

10. Use of a drug combination according to any one of claims 1 to 9 for the manufacture of a drug for treating hepatitis B virus infection.

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