Internal cyclic sulphiamidine amide-aryl amide compound and use thereof for treating hepatitis B
View Patent ↗The invention relates to an internal cyclic sulphiamidine amide-aryl amide compound and a use thereof for treating hepatitis B. Specifically, disclosed is a compound that may act as an HBV replication inhibitor and that has a structure represented by chemical formula (L), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvent thereof. See the description for detailed definitions of each group. The present invention also relates to a pharmaceutical composition containing the compound and a use thereof for treating hepatitis B.
1 . A compound represented by formula L, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein the compound L is of the following structure:
wherein:
is a substituted or unsubstituted five- or six-membered aromatic ring, or a substituted or unsubstituted five- or six-membered heteroaromatic ring;
X 1 is —CR═ or —N═, X 2 is —NR—; and each R is independently H or C 1 -C 4 alkyl;
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkyl, and substituted or unsubstituted C 1 -C 4 alkoxy; wherein the substituted means that hydrogen atoms on the group are substituted by one or more substituents selected from the group consisting of halogen and C 1 -C 4 alkyl;
R 5 and R 6 are each independently selected from the group consisting of H, halogen, —CN, hydroxyl, amino, carboxyl, —(C═O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
R a is selected from the group consisting of (a) cyclopropyl, (b) methylene cyclopropyl, (c) methyl substituted by 4-fluorophenyl and (d) methyl substituted by 4-methoxyphenyl;
unless otherwise specified, “substituted” means that the group is substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, halogenated C 3 -C 8 cycloalkyl, oxo, —CN, hydroxyl, amino, carboxyl, and the following groups unsubstituted or substituted by one or more halogen, C 1 -C 6 alkoxy, or any combination thereof: C 6 -C 10 aryl, halogenated C 6 -C 10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O.
2 . The compound of claim 1 , a stereoisomers or tautomers thereof, or a pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X 1 is —CR═, X 2 is —NR—; and R is H or C 1 -C 4 alkyl.
3 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:
ESI-MS,
No.
Structure
(M + H)
Remark
100a01
402
Peak1 (HPLC)
100a02
402
Peak2 (HPLC)
100a03
400
Peak1 (HPLC)
100a04
400
Peak2 (HPLC)
100a05
395
Peak1 (HPLC)
100a06
395
Peak2 (HPLC)
100a07
393
Peak1 (HPLC)
100a08
393
Peak2 (HPLC)
100a09
413
Peak1 (HPLC)
100a10
413
Peak2 (HPLC)
100a11
411
Peak1 (HPLC)
100a12
411
Peak2 (HPLC)
100b01
416
Peak1 (HPLC)
100b02
416
Peak2 (HPLC)
100b03
414
Peak1 (HPLC)
100b04
414
Peak2 (HPLC)
100b05
409
Peak1 (HPLC)
100b06
409
Peak2 (HPLC)
100b07
407
Peak1 (HPLC)
100b08
407
Peak2 (HPLC)
100b09
427
Peak1 (HPLC)
100b10
427
Peak2 (HPLC)
100b11
425
Peak1 (HPLC)
100b12
425
Peak2 (HPLC)
100c01
470
Peak1 (HPLC)
100c02
470
Peak2 (HPLC)
100c03
468
Peak1 (HPLC)
100c04
468
Peak2 (HPLC)
100c05
463
Peak1 (HPLC)
100c06
463
Peak2 (HPLC)
100c07
461
Peak1 (HPLC)
100c08
461
Peak2 (HPLC)
100c09
481
Peak1 (HPLC)
100c10
481
Peak2 (HPLC)
100c11
479
Peak1 (HPLC)
100c12
479
Peak2 (HPLC)
100c13
482
Peak1 (HPLC)
100c14
482
Peak2 (HPLC)
100c15
480
Peak1 (HPLC)
100c16
480
Peak2 (HPLC)
100c17
475
Peak1 (HPLC)
100c18
475
Peak2 (HPLC)
100c19
473
Peak1 (HPLC)
100c20
473
Peak2 (HPLC)
wherein Peak 1 and Peak 2 refer to the order of the enantiomers' peaks in reversed-phase HPLC, wherein Peak 1 is the first peak in the enantiomer, and Peak 2 is the latter peak of the enantiomer.
4 . A pharmaceutical composition, which comprises (1) the compound, or the stereoisomer thereof, tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate of claim 1 and (2) pharmaceutically acceptable carriers.
5 . A method for preventing and/or treating hepatitis B virus infection in a subject, the method comprising administering to a subject in need thereof an effective amount of the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of claim 1 , or a pharmaceutical composition comprising the same and a pharmaceutically acceptable carrier.
6 . A hepatitis B virus inhibitor which comprises a compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of claim 1 .
7 . A method for in vitro inhibiting hepatitis B virus, which comprises the step: contacting the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of claim 1 with hepatitis B virus so as to inhibit the replication of hepatitis B virus.