WO2021018207A1 - 一类用于治疗和/或预防乙型肝炎病毒感染的化合物及其制备方法和应用 - Google Patents
一类用于治疗和/或预防乙型肝炎病毒感染的化合物及其制备方法和应用 Download PDFInfo
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- WO2021018207A1 WO2021018207A1 PCT/CN2020/105562 CN2020105562W WO2021018207A1 WO 2021018207 A1 WO2021018207 A1 WO 2021018207A1 CN 2020105562 W CN2020105562 W CN 2020105562W WO 2021018207 A1 WO2021018207 A1 WO 2021018207A1
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- Prior art keywords
- compound
- alkyl
- group
- hydrogen
- halogen
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- 238000002360 preparation method Methods 0.000 title abstract description 36
- 208000002672 hepatitis B Diseases 0.000 title abstract description 7
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- 229910052717 sulfur Inorganic materials 0.000 claims description 121
- 125000005842 heteroatom Chemical group 0.000 claims description 109
- 229910052736 halogen Inorganic materials 0.000 claims description 97
- 150000002367 halogens Chemical class 0.000 claims description 97
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 94
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- 150000002431 hydrogen Chemical class 0.000 claims description 79
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 49
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
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- 125000001424 substituent group Chemical group 0.000 claims description 35
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- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 14
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- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Definitions
- the present invention relates to the field of biomedicine, in particular to a class of compounds used for the treatment and/or prevention of hepatitis B virus infection and preparation methods and applications thereof.
- Such compounds can significantly reduce the HBV surface antigen (HBsAg) in the body while being effective Inhibit the replication of HBV virus.
- HBV surface antigen HBV surface antigen
- HBV Hepatitis B
- HBsAg the high serum level of HBsAg
- serological clearance of HBsAg is considered to be one of the clinical criteria for hepatitis B cure.
- the present invention provides a new type of compound, which can effectively inhibit the secretion of HBsAg in HBV infected cells and reduce the viral load and virus replication of HBV patients.
- the compounds of the present invention have higher activity, better in vivo efficacy, better safety, better pharmacokinetic properties and better druggability.
- the present invention also provides a pharmaceutical composition containing the novel compound and a method of using the compound or composition to inhibit HBV replication and treat diseases related to or caused by HBV.
- the first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt or enantiomer or tautomer thereof:
- X is selected from the following group: N, CH;
- R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl and halogen substituted C 1 -C 6 alkyl;
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 containing 1, 2 or 3 heteroatoms selected from N, O, S -10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C 6 -C 12 aryl; the alkyl, cycloalkyl , Heterocycloalkyl, heteroaryl, aryl optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkane Group, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing Substitution of 1, 2 or 3 heteroatoms selected from N, O, S
- Each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl.
- X is selected from the following group: N, CH;
- R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl and halogen substituted C 1 -C 6 alkyl;
- R 4 is selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, S Alkyl groups, 5-10 membered heteroaryl groups and C 6 -C 12 aryl groups containing 1, 2 or 3 heteroatoms selected from N, O, S, the alkyl groups, cycloalkyl groups, heterocycloalkyl groups , Heteroaryl and aryl are optionally further selected from hydrogen, halogen, hydroxyl, carbonyl, amine, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-10 membered heterocycloalkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing 1, 2 Or 3 substituents of 5-10
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 containing 1, 2 or 3 heteroatoms selected from N, O, S -10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C 6 -C 12 aryl; the alkyl, cycloalkyl , Heterocycloalkyl, heteroaryl, aryl optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkane Group, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing Substitution of 1, 2 or 3 heteroatoms selected from N, O, S
- Each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl.
- X is selected from the following group: N, CH;
- R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl and halogen substituted C 1 -C 6 alkyl;
- R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl
- R 4 is selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, the alkyl and cycloalkyl are optionally further selected from 1-3 hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl substituent substituted;
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl.
- X is N
- R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and halogen substituted C 1 -C 6 alkyl;
- R 2 is selected from the following group: halogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 selected from N, O, S Heteroatomic 5-10 membered heteroaryl; the alkoxy, cycloalkyl, alkyl, and heteroaryl are optionally further selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl substituents are substituted.
- X is N
- R 1 is selected from the group consisting of hydrogen and halogen
- R 2 is halogen
- R 1 is selected from the following group: -H, -F, -CF 3 ;
- R 2 is selected from the following group: -Cl, -CHF 2 , -CH 2 OCH 3 , -CH 3 .
- R 1 is selected from the following group: -H, -F;
- R 2 is -Cl.
- R 4 is selected from the following group: C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 containing 1, 2 or 3 heteroatoms selected from N, O, S -10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl
- the group is optionally further selected from hydrogen, halogen, hydroxy, carbonyl, amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 3-10 membered heterocycloalkyl groups selected from heteroatoms of N, O, S, halogen-substituted C 1 -C 6 alkyl groups, C 1 -C 6 alkoxy groups, containing 1, 2 or 3 selected from N , O, and S heteroatoms are substituted by substituents of 5-10 membered
- X is N
- R 1 is selected from the following group: -H, -F, -CF 3 ;
- R 2 is selected from the following group: -Cl, -CHF 2 , -CH 2 OCH 3 , -CH 3 ;
- R 3 is selected from the following group: C 3 -C 10 cycloalkyloxy, 3-10 membered heterocycloalkyloxy containing 1, 2 or 3 heteroatoms selected from N, O, S, C 3- C 10 cycloalkyl N(R 8 )-, 3-10 membered heterocycloalkyl N(R 8 )- containing 1, 2 or 3 heteroatoms selected from N, O, S, containing 1, 2 or 5-10 membered heteroaryl groups and C 6 -C 12 aryl groups with 3 heteroatoms selected from N, O and S; the cycloalkyl, heterocycloalkyl, heteroaryl and aryl groups optionally further With 1, 2 or 3 selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 selected from N, O, S Heteroatomic 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2
- R 4 is selected from the following group: C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S , 5-10 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O, S, the alkyl group, cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally further divided by 1 -3 selected from hydrogen, halogen, hydroxyl, carbonyl, amine, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 selected from N, O, S Heteroatomic 3-10 membered heterocycloalkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 heteroatoms selected from N, O, S Substituents of 5-10 membered
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 containing 1, 2 or 3 heteroatoms selected from N, O, S -10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C 6 -C 12 aryl; the alkyl, cycloalkyl , Heterocycloalkyl, heteroaryl, aryl optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkane Group, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing Substitution of 1, 2 or 3 heteroatoms selected from N, O, S
- Each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl.
- X is N
- R 1 is -H
- R 2 is -Cl
- R 4 is C 1 -C 6 alkyl
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl.
- R 4 is tert-butyl
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl.
- R 4 is tert-butyl
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
- R 4 is tert-butyl
- R 3 is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein the heteroaryl group is optionally further selected from hydrogen, halogen, C 1 -C 6 alkyl substituents are substituted.
- R 4 is tert-butyl
- R 3 is a C 3 -C 6 cycloalkyloxy group; the cycloalkyl group is further selected from 1, 2 or 3 Substituent substitution;
- R 5 is C 1 -C 6 alkylene
- R 6 is a C 1 -C 6 alkyl group.
- R 4 is tert-butyl
- R 3 is a 3-7 membered heterocycloalkyloxy group containing 1, 2 or 3 heteroatoms selected from N, O, and S.
- R 4 is tert-butyl
- R 3 is selected from the following group of substituted or unsubstituted groups: Wherein said substitution refers to substitution by 1-3 C 1 -C 6 alkyl groups.
- R 4 is tert-butyl
- R 3 is selected from the following group:
- the structure is as shown in formula I-R-1:
- R 1 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl and halogen substituted C 1 -C 6 alkyl;
- R 2 is selected from the following group: halogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 selected from N, O, S Heteroatomic 5-10 membered heteroaryl group; the C 1 -C 6 alkoxy group, cycloalkyl group, alkyl group, heteroaryl group is optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amine Substituents of cyano, cyano, C 1 -C 6 alkyl;
- R 3 is selected from the following group: C 3 -C 10 cycloalkyloxy, 3-10 membered heterocycloalkyloxy containing 1, 2 or 3 heteroatoms selected from N, O, S, C 3- C 10 cycloalkyl N(R 8 )-, 3-10 membered heterocycloalkyl N(R 8 )- containing 1, 2 or 3 heteroatoms selected from N, O, S, containing 1, 2 or 5-10 membered heteroaryl groups and C 6 -C 12 aryl groups with 3 heteroatoms selected from N, O and S; the cycloalkyl, heterocycloalkyl, heteroaryl and aryl groups optionally further With 1, 2 or 3 selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 selected from N, O, S Heteroatomic 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2
- R 5 is C 1 -C 6 alkylene
- R 6 and R 7 are independently selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 containing 1, 2 or 3 heteroatoms selected from N, O, S -10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C 6 -C 12 aryl; the alkyl, cycloalkyl , Heterocycloalkyl, heteroaryl, aryl optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkane Group, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing Substitution of 1, 2 or 3 heteroatoms selected from N, O, S
- R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl.
- R 1 is selected from the group consisting of hydrogen, halogen, and methyl substituted with 1-3 halogens;
- R 2 is selected from the following group: -Cl, -CHF 2 , -CH 2 OCH 3 , -CH 3 .
- R 2 is selected from the group consisting of halogen, methyl substituted with 1-3 halogens, and methoxy.
- R 1 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl and halogen substituted C 1 -C 6 alkyl;
- R 2 is selected from the following group: halogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 selected from N, O, S Heteroatomic 5-10 membered heteroaryl group; the C 1 -C 6 alkoxy group, cycloalkyl group, alkyl group, heteroaryl group is optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amine Substituents of cyano, cyano, C 1 -C 6 alkyl;
- R 5 is a C 1 -C 6 alkylene group;
- R 6 and R 7 are selected from the following group: hydrogen, C 1 -C 6 alkyl;
- R 4 is selected from the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, S Alkyl groups, 5-10 membered heteroaryl groups and C 6 -C 12 aryl groups containing 1, 2 or 3 heteroatoms selected from N, O, S, the alkyl groups, cycloalkyl groups, heterocycloalkyl groups , Heteroaryl and aryl are optionally further selected from hydrogen, halogen, hydroxyl, carbonyl, amine, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-10 membered heterocycloalkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing 1, 2 Or 3 substituents of 5-10
- R 2 is selected from the following group: hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 selected from N, O , S heteroatom 3-10 membered heterocycloalkyl, halogen substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 selected from N, O, S Heteroatomic 5-10 membered heteroaryl, C 6 -C 12 aryl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyl S(O) m -; the alkoxy, cycloalkane Group, alkyl group, heterocycloalkyl group, heteroaryl group, aryl group is optionally further selected from 1-3 hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 3- C 10 cycloalkyl, 3-10 membered heterocyclo
- R 1 is selected from the group consisting of hydrogen, halogen, and methyl substituted with 1-3 halogens.
- R 2 is selected from the following group: hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 selected from N, O , S heteroatom 3-10 membered heterocycloalkyl, halogen substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 selected from N, O, S Heteroatomic 5-10 membered heteroaryl, C 6 -C 12 aryl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyl S(O) m -; the alkyl group, cycloalkyl group , Heterocycloalkyl, alkoxy, heteroaryl, aryl optionally further selected from 1-3 halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycloalkyl
- R 2 is selected from the following group: -Cl, -CHF 2 , -CH 2 OCH 3 , -CH 3 .
- R 4 is selected from the following group: C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 containing 1, 2 or 3 heteroatoms selected from N, O, S -10 membered heterocycloalkyl group, 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S and C 6 -C 12 aryl group, the alkyl group, cycloalkyl group , Heterocycloalkyl, heteroaryl and aryl are optionally further selected from hydrogen, halogen, hydroxyl, carbonyl, amine, cyano, C 1 -C 6 alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, halogen substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy , Substituents of 5-10 membered heteroaryl containing
- the structure is as shown in formula I-R-3:
- R 1 is selected from the group consisting of hydrogen, halogen, and methyl substituted with 1-3 halogens;
- Ring A is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein the heteroaryl group is optionally further selected from halogen, hydroxy, carbonyl, Amino, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, Substituents substituted by halogen substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S;
- R 4 is selected from the following group: C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S , 5-10 membered heteroaryl groups and C 6 -C 12 aryl groups containing 1, 2 or 3 heteroatoms selected from N, O, S, the alkyl, cycloalkyl, heterocycloalkyl, hetero Aryl and aryl are optionally further selected from hydrogen, halogen, hydroxyl, carbonyl, amine, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-10 membered heterocycloalkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, containing 1, 2 or 3 Substituents of 5-10 membered heteroaryl groups
- the second aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more of the compounds of the first aspect of the present invention or their pharmaceutically acceptable salts or their enantiomers Constructs or tautomers.
- the third aspect of the present invention provides a use of the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or its enantiomers or tautomers for use in a group selected from the group consisting of the use of:
- the treatment target is a mammal, such as a human.
- the fourth aspect of the present invention provides an HBsAg inhibitor, comprising an inhibitory effective amount of one or more of the compounds described in the first aspect of the present invention or their pharmaceutically acceptable salts or their enantiomers or Tautomers.
- the fifth aspect of the present invention provides a method for treating or preventing HBV infection, which comprises the steps of: administering to a patient in need a therapeutically or preventively effective amount of one or more of the compounds described in the first aspect of the present invention or their pharmacy The above acceptable salt or its enantiomer or tautomer.
- the sixth aspect of the present invention provides a method for inhibiting the production or secretion of HBsAg, comprising the steps of: administering an inhibitory effective amount of one or more of the compounds described in the first aspect of the present invention or their pharmaceutically Acceptable salt or its enantiomer or tautomer.
- the inventors unexpectedly prepared a novel structure, higher activity, better in vivo efficacy, better safety, better pharmacokinetic properties, and better pharmacokinetic properties through structural design. Good pharmaceutical compound. On this basis, the inventor completed the present invention.
- halogen refers to F, Cl, Br or I.
- C 1 -C 6 alkyl refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, tert-butyl, neopentyl, tert-pentyl, or similar groups.
- cycloalkyl refers to saturated monocyclic groups, fused ring groups, and bridging groups having 3 to 10 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- C 3 -C 10 cycloalkyl can optionally be up to four selected from halogen, oxo, CN, amino, hydroxyl, C 1 -C 3 alkyl, -OR*, -NR*2, -SR*, -SO 2 R*, -COOR* and -CONR*2 are substituted with groups, wherein each R* is independently H or C 1-3 alkyl.
- the heterocyclic group containing a sulfur atom may optionally be substituted with one or two oxo groups on the sulfur.
- C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, and includes non-limitingly methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc. Preferably it is a C1-C4 alkoxy group.
- heterocycloalkyl refers to a non-aromatic cyclic group formed by one or more heteroatoms selected from nitrogen, oxygen, and sulfur and one or more carbon atoms, including monocyclic Groups, fused ring groups and bridging groups.
- the heterocyclic group may be a 3- to 10-membered ring system containing 1 to 3 selected from nitrogen, oxygen, and sulfur, wherein preferably at least one heteroatom is selected from nitrogen.
- heterocycloalkyl groups include, but are not limited to, pyrrolidine, piperidine, piperazine, pyrrolidone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1 ,4-oxathiolane, 8-aza-bicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-aza- Bicyclo[3.2.1]octane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 2-oxa-5-aza-bicyclo[2.2.1]heptane, 2,5 -Diaza-bicyclo[2.2.1]heptane, azetidine, ethylene dioxane, oxetane or thiazole.
- the heterocyclic group has 1-2 heteroatoms selected from N, O, and S as ring members, and 4-7 ring atoms, and optionally up to four A group selected from halogen, oxo, CN, amino, hydroxyl, C 1 -C 3 alkyl, -OR*, -NR*2, -SR*, -SO 2 R*, -COOR* and -CONR*2 Group substitution, where each R* is independently H or C 1-3 alkyl.
- the heterocyclic group containing a sulfur atom may optionally be substituted with one or two oxo groups on the sulfur.
- aromatic ring or “aryl” have the same meaning, and are preferably “C6-C12 aryl”.
- C6-C12 aryl group refers to an aromatic ring group having 6 to 12 carbon atoms that does not contain heteroatoms in the ring, such as phenyl, naphthyl and the like.
- Aryl can optionally be selected from up to four selected from halogen, oxo, CN, amino, hydroxyl, C 1 -C 3 alkyl, -OR*, -NR*2, -SR*, -SO 2 R*, -COOR* and -CONR*2 groups are substituted, where each R* is independently H or C 1-3 alkyl.
- the heterocyclic group containing a sulfur atom may optionally be substituted with one or two oxo groups on the sulfur.
- heteroaryl refers to a fused or non-fused aromatic cyclic group formed by one or more heteroatoms selected from oxygen, nitrogen, sulfur and one or more carbon atoms, at least one of which is
- the ring is a five to eight membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, preferably at least one heteroatom is selected from nitrogen.
- the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other, provided that all The ring of the group does not contain two adjacent O or S atoms.
- heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl , Pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, etc.
- Heteroaryl may be selected from up to four selected from halogen, oxo, CN, amino, hydroxyl, C 1 -C 3 alkyl, -OR*, -NR*2, -SR*, -SO 2 R* , -COOR* and -CONR*2, where each R* is independently H or C 1-3 alkyl.
- the heterocyclic group containing a sulfur atom may optionally be substituted with one or two oxo groups on the sulfur.
- halo refers to substitution by halogen.
- amino is a -NH 2 group.
- carbonyl has the following structure:
- amino group is a -NR 1 *R 2 * group.
- R 1 * and R 2 * are independently H, C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl.
- bridged cycloalkyl refers to a polycyclic group having bridging carbon atoms, such as
- trifluoromethyl is a -CF 3 group.
- trifluoromethoxy is an -OCF 3 group.
- a group when a group is defined as "may be further substituted by”, it may or may not be substituted by one or more groups selected from the group consisting of alkyl, alkoxy, halogen, Hydroxyl, amino.
- groups selected from the group consisting of alkyl, alkoxy, halogen, Hydroxyl, amino.
- any group containing one or more substituents will not be introduced into any substitution or substitution pattern that cannot exist in space and/or cannot be synthesized.
- substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
- the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
- a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
- substituents contemplated by the present invention are those that are stable or chemically achievable.
- the substituents such as (but not limited to): halogen, hydroxyl, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
- the present invention provides a class of compounds that inhibit the secretion of HBsAg, which is expected to be used to treat HBV infection and reduce the incidence of severe liver diseases caused by HBV infection.
- the compounds reported in the present invention have higher activity, better in vivo efficacy, better safety, and better pharmacokinetic properties, as well as better medicinal properties. Attributes.
- the present invention provides a compound of formula I or a pharmaceutically acceptable salt or enantiomer or tautomer thereof:
- each group is as defined above.
- the compound is selected from the following group:
- the compound is selected from the following group:
- pharmaceutically acceptable salts refers to those salts that retain the biological effectiveness and properties of the parent compound, which have the desired pharmaceutical activity and are biologically and otherwise undesirable. .
- the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or a base suitable for use as a medicine.
- Pharmaceutically acceptable salts include inorganic salts and organic salts.
- a preferred class of salts are the salts of the compounds of this invention with acids.
- Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
- a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine.
- alkali metal salt such as sodium or potassium salt
- alkaline earth metal salt such as magnesium salt or calcium salt
- ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
- methylamine salt such as sodium or potassium salt
- alkaline earth metal salt such as magnesium salt or calcium salt
- Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof or an enantiomer or tautomer thereof for use in inhibiting hepatitis B virus.
- Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof or an enantiomer or tautomer thereof for use in the treatment of hepatitis B virus infection in mammals, particularly humans.
- the compound of the present invention can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
- These dosage forms are suitable for oral administration, rectal administration, topical administration, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.).
- dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
- the compounds of the present invention contained in these preparations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
- the above-mentioned dosage forms can be prepared from the active compound and one or more pharmaceutically acceptable carriers through general pharmaceutical methods.
- a pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
- the above-mentioned carrier needs to be compatible with the active compound or other excipients.
- commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, calcium carbonate, calcium phosphate, starch, cellulose and its derivatives, glucose, sucrose, gelatin and the like.
- Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, vegetable oil, ethylene glycol, polyethylene glycol, and the like.
- the active compound can form a solution or a suspension with the aforementioned carriers.
- the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
- the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
- the "one dose" is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
- pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
- Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
- polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
- emulsifiers such as Tween
- wetting agents such as sodium lauryl sulfate
- coloring agents such as sodium lauryl sulfate
- flavoring agents such as pepperminophen, sorbitol, etc.
- antioxidants
- the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
- the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
- Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvent, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycerol, or
- Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
- composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
- the specific administration method and dosage form depend on the physical and chemical properties of the compound itself and the severity of the applied disease.
- the term "therapeutically effective amount” may be one or more of one or more of the symptoms of the disease or disorder in the subject to a certain extent, related to the disease or disorder, or one or more of its cause. Or the amount of biochemical parameters that partially or completely return to normal, and/or reduce the likelihood of the onset of a disease or disorder.
- the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
- the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
- the daily administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
- the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
- the present invention has the following main advantages:
- the compound of the present invention has higher activity, better in vivo pharmacodynamics, better safety, better pharmacokinetic properties and better medicinal properties.
- the aqueous phase was extracted with dichloromethane (3x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by concentration was purified by pre-HPLC (0.1% ammonia/acetonitrile/water) to obtain the compound EXP 12A (5.3 mg, yield 14%) and EXP 12B (6.5 mg, yield 17%).
- the aqueous phase was extracted with dichloromethane (3x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by concentration was purified by pre-HPLC (0.1% ammonia/acetonitrile/water) to obtain the compound EXP 21 (3.8mg, 32%) is a white solid.
- HBsAg hepatitis B virus surface antigen
- HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330032; 10% serum, Invitrogen-10099141; 100units/ml penicillin and 100 ⁇ g/ml streptomycin, Hyclone-SV30010; 1% non-essential amino acids, Invitrogen-11140050; 2mM L-GLUTAMINE, Invitrogen-25030081; 300 ⁇ g/ml Geneticin, Invitrogen-10131027.
- DMEM/F12 Invitrogen-11330032
- 10% serum Invitrogen-10099141
- 100units/ml penicillin and 100 ⁇ g/ml streptomycin Hyclone-SV30010
- 1% non-essential amino acids Invitrogen-11140050
- 2mM L-GLUTAMINE Invitrogen-25030081
- 300 ⁇ g/ml Geneticin Invitrogen-10131027.
- the compound was first diluted with DMSO, a 3-fold gradient dilution total of 8 concentrations, and then added to the medium for further dilution. Then add the medium containing different concentrations of the compound to the culture wells, and double the wells. The final concentration of DMSO in the culture broth is 0.5%. Only 0.5% DMSO was used as a no-drug control.
- %Inh. (1-HBsAg value in sample/HBsAg value of 0.5% DMSO control) ⁇ 100%.
- Example 30 Pharmacokinetic study of compound EXP 2 and comparative example 1
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Abstract
Description
Claims (14)
- 式I化合物或其药学上可接受的盐或其对映异构体或互变异构体:其中,X选自下组:N、CH;R 1选自下组:氢、卤素、羟基、C 1-C 6烷基和卤素取代的C 1-C 6烷基;R 2选自下组:氢、卤素、氰基、C 1-C 6烷基;R 3选自下组:C 3-C 10环烷基氧基、含1、2或3个选自N、O、S的杂原子的3-10元杂环烷基氧基、含1、2或3个选自N、O、S的杂原子的5-10元杂芳基;所述环烷基、杂环烷基、杂芳基任选地进一步被1、2或3个选自氢、卤素、羟基、氰基、=O、C 1-C 6烷基、C 3-C 10环烷基、含1、2或3个选自N、O、S的杂原子的3-10元杂环烷基、 的取代基取代;R 4选自下组:氢、C 1-C 6烷基、C 3-C 10环烷基,所述烷基、环烷基任选地进一步被1-3个选自氢、卤素、C 1-C 6烷基、C 3-C 10环烷基的取代基取代;R 5为C 1-C 6亚烷基;R 6、R 7独立地选自下组:氢、C 1-C 6烷基。
- 根据权利要求1所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中与R 4连接的手性碳的绝对构型如式I-R所示:其中,X选自下组:N、CH;R 1选自下组:氢、卤素、羟基、C 1-C 6烷基和卤素取代的C 1-C 6烷基;R 2选自下组:氢、卤素、氰基、C 1-C 6烷基;R 3选自下组:C 3-C 10环烷基氧基、含1、2或3个选自N、O、S的杂原子的3-10元杂环烷基氧基、含1、2或3个选自N、O、S的杂原子的5-10元杂芳基;所述 环烷基、杂环烷基、杂芳基任选地进一步被1、2或3个选自氢、卤素、羟基、氰基、=O、C 1-C 6烷基、C 3-C 10环烷基、 的取代基取代;R 4选自下组:氢、C 1-C 6烷基、C 3-C 10环烷基,所述烷基、环烷基任选地进一步被1-3个选自氢、卤素、C 1-C 6烷基、C 3-C 10环烷基的取代基取代;R 5为C 1-C 6亚烷基;R 6、R 7独立地选自下组:氢、C 1-C 6烷基。
- 根据权利要求2所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中:X为N;R 1选自下组:氢、卤素;R 2为卤素。
- 根据权利要求3所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中:R 1选自下组:-H、-F;R 2为-Cl。
- 根据权利要求5所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中:R 4为叔丁基;R 3为含1、2或3个选自N、O、S的杂原子的5-6元杂芳基,其中杂芳基任选地进一步被1-3个选自氢、卤素、C 1-C 6烷基的取代基取代。
- 根据权利要求5所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中,R 4为叔丁基;R 3为含1、2或3个选自N、O、S的杂原子的3-7元杂环烷基氧基。
- 一种药物组合物,其特征在于,包含药学上可接受的载体和一种或多种权利要求1所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体。15、一种权利要求1所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体的用途,其特征在于,用于选自下组的用途:1)用于治疗或预防HBV感染;2)用于制备用于治疗或预防HBV感染的药物;3)用于抑制HBsAg的生成或分泌。
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