Endocyclic thiamidinoamide-arylamide compound and use thereof for treating hepatitis B
Disclosed are an endocyclic thiamidinoamide-arylamide compound and a pharmaceutical composition comprising the compound described above, and the use of the compound or pharmaceutical composition in the treatment of hepatitis B. In particular, disclosed is a compound that can be used as an HBV replication inhibitor and has the structure as shown in chemical formula (L), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
1. A compound represented by formula L, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
is a substituted or unsubstituted five or six membered ring, wherein the five or six membered ring optionally contains one or more heteroatoms selected from the group consisting of O, S, N or P; the substituted means that the hydrogen atoms on the group are substituted by one or more substituents selected from the group consisting of C1-C3 alkyl, C3-C4 cycloalkyl, cyano, or halogen;
is a substituted or unsubstituted five- or six-membered aromatic ring, or a substituted or unsubstituted five- or six-membered heteroaromatic ring;
X is —CR a R b —;
Y is substituted or unsubstituted C1-C7 alkylene, or substituted or unsubstituted C2-C7 alkenylene, wherein the substituent is selected from the group consisting of C1-C4 alkyl, hydroxyl;
Z is selected from the group consisting of O, S, N, and P, or Z is a C—C single bond;
W is NRc or none;
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 C1-C4 alkyl, substituted or unsubstituted C1-C4 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 C1-C4 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 C 6 -C 10 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 and R b are each independently 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 1 -C 6 alkoxy-alkyl, 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 C 6 -C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
Rc is 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 C 6 -C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
“substituted” means that the group substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, —CN, hydroxyl, amino, carboxyl, and the following groups unsubstituted or substituted by one or more substituents: C6-C10 aryl, halogenated C6-C10 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; and
the substituent is selected from the group consisting of halogen and C1-C6 alkoxy.
2. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is of a formula selected from the group consisting L-1, L-2, L-3 and L-4:
in each formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
the definitions of A ring, B ring, X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described in claim 1 .
3. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula I has a structure shown in the following formula II:
wherein X 1 is —CR═ or —N═, X 2 is —NR—; and R is H or C1-C4 alkyl.
4. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the X 2 is —NCH 3 —.
5. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula I has the following structure:
6. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula I has a structure shown by the following formula IV-1 or IV-2:
7. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R a is selected from the group consisting of substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, and substituted or unsubstituted C1-C6 alkoxy-alkyl; and
R b is H.
8. 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 following:
No.
Structure
Remark
10a1
Peak1 (HPLC)
10a2
Peak2 (HPLC)
10b1
Peak1 (HPLC)
10b2
Peak2 (HPLC)
10c1
Peak1 (HPLC)
10c2
Peak2 (HPLC)
10d1
Peak1 (HPLC)
10d2
Peak2 (HPLC)
10e1
Peak1 (HPLC)
10e2
Peak2 (HPLC)
10f1
Peak1 (HPLC)
10f2
Peak2 (HPLC)
10g1
Peak1 (HPLC)
10g2
_
Peak2 (HPLC)
10h1
Peak1 (HPLC)
10h2
Peak2 (HPLC)
10i1
Peak1 (HPLC)
10i2
Peak2 (HPLC)
10j1
Peak1 (HPLC)
10j2
Peak2 (HPLC)
10k1
Peak1 (HPLC)
10k2
Peak2 (HPLC)
10m1
Peak1 (HPLC)
10m2
Peak2 (HPLC)
10n1
Peak1 (HPLC)
10n2
Peak2 (HPLC)
10o1
Peak1 (HPLC)
10o2
Peak2 (HPLC)
10p1
Peak1 (HPLC)
10p2
Peak2 (HPLC)
10q1
Peakl (HPLC)
10q2
Peak2 (HPLC)
10r1
Peakl (HPLC)
10r2
Peak2 (HPLC)
10s1
Peakl (HPLC)
10s2
Peak2 (HPLC)
10t1
Peakl (HPLC)
10t2
Peak2 (HPLC)
10u1
Peak1 (HPLC)
10u2
Peak2 (HPLC)
10v1
Peak1 (HPLC)
10v2
Peak2 (HPLC)
10w1
Peak1 (HPLC)
10w2
Peak2 (HPLC)
10x1
Peak1 (HPLC)
10x2
Peak2 (HPLC)
10y1
Peakl (HPLC)
10y2
Peak2 (HPLC)
10z1
Peakl (HPLC)
10z2
Peak2 (HPLC)
10aa1
Peakl (HPLC)
10aa2
Peak2 (HPLC)
10bb1
Peakl (HPLC)
10bb2
Peak2 (HPLC)
10cc1
Peak1 (HPLC)
10cc2
Peak2 (HPLC)
10dd1
Peak1 (HPLC)
10dd2
Peak2 (HPLC)
10ee1
Peak1 (HPLC)
10ee2
Peak2 (HPLC)
10ff1
Peak1 (HPLC)
10ff2
Peak2 (HPLC)
10gg1
Peak1 (HPLC)
10gg2
Peak2 (HPLC)
10hh1
Peak1 (HPLC)
10hh2
Peak2 (HPLC)
10ii1
Peak1 (HPLC)
10ii2
Peak2 (HPLC)
10ji1
Peak1 (HPLC)
10jj2
Peak2 (HPLC)
10kk1
Peak1 (HPLC)
10kk2
Peak2 (HPLC)
10mm1
Peak1 (HPLC)
10mm2
Peak2 (HPLC)
10nn1
Peak1 (HPLC)
10nn2
Peak2 (HPLC)
10oo1
Peak1 (HPLC)
10oo2
Peak2 (HPLC)
10pp1
Peak1 (HPLC)
10pp2
Peak2 (HPLC)
10qq1
Peak1 (HPLC)
10qq2
Peak2 (HPLC)
10rr1
Peak 1 (HPLC)
10rr2
Peak2 (HPLC)
10ss1
Peak
1 (HPLC)
10ss2
Peak2 (HPLC)
10tt1
Peakl (HPLC)
10tt2
Peak2 (HPLC)
10uu1
Peakl (HPLC)
10uu2
Peak2 (HPLC)
10vv1
Peakl (HPLC)
10vv2
Peak2 (HPLC)
10ww1
Peakl (HPLC)
10ww2
Peak2 (HPLC)
10xx1
Peakl (HPLC)
10xx2
Peak2 (HPLC)
10yy1
Peakl (HPLC)
10yy2
Peak2 (HPLC)
10zz1
Peakl (HPLC)
10zz2
Peak2 (HPLC)
10aaa1
Peakl (HPLC)
10aaa2
Peak2 (HPLC)
10bbb1
Peakl (HPLC)
10bbb2
Peak2 (HPLC)
10ccc1
Peakl (HPLC)
10ccc2
Peak2 (HPLC)
10ddd1
Peakl (HPLC)
10ddd2
Peak2 (HPLC)
10eee1
Peakl (HPLC)
10eee2
Peak2 (HPLC)
10fff1
Peakl (HPLC)
10fff2
Peak2 (HPLC)
10ggg1
Peakl (HPLC)
10ggg2
Peak2 (HPLC)
10hhh1
Peakl (HPLC)
10hhh2
Peak2 (HPLC)
10iii1
Peakl (HPLC)
10iii2
Peak2 (HPLC)
10jjj1
Peakl (HPLC)
10jjj2
Peak2 (HPLC)
10kkk1
Peakl (HPLC)
10kkk2
Peak2 (HPLC)
10mmm1
Peakl (HPLC)
10mmm2
Peak2 (HPLC)
10nnn1
Peakl (HPLC)
10nnn2
Peak2 (HPLC)
10ooo1
Peak 1 (HPLC)
10ooo2
Peak2 (HPLC)
10ppp1
Peak 1 (HPLC)
10ppp2
Peak2 (HPLC)
10qqq1
Peak 1 (HPLC)
10qqq2
Peak2 (HPLC)
10rrr1
Peak 1 (HPLC)
10rrr2
Peak2 (HPLC)
10sss1
Peakl (HPLC)
10sss2
Peak2 (HPLC)
10ttt1
Peakl (HPLC)
10ttt2
Peak2 (HPLC)
10uuu1
Peakl (HPLC)
10uuu2
Peak2 (HPLC)
10vvv1
Peakl (HPLC)
10vvv2
Peak2 (HPLC)
10www1
Peakl (HPLC)
10www2
Peak2 (HPLC)
10xxx1
Peakl (HPLC)
10xxx2
Peak2 (HPLC)
20a1
Peakl (HPLC)
20a2
Peak2 (HPLC)
20b1
Peakl (HPLC)
20b2
Peak2 (HPLC)
20c1
Peak1 (HPLC)
20c2
Peak2 (HPLC)
20d1
Peak1 (HPLC)
20d2
Peak2 (HPLC)
20e1
Peak1 (HPLC)
20e2
Peak2 (HPLC)
20f1
Peak1 (HPLC)
20f2
Peak2 (HPLC)
20g1
Peak1 (HPLC)
20g2
Peak2 (HPLC)
20h1
Peak1 (HPLC)
20h2
Peak2 (HPLC)
20i1
Peak1 (HPLC)
20i2
Peak2 (HPLC)
20j1
Peak1 (HPLC)
20j2
Peak2 (HPLC)
20k1
Peak1 (HPLC)
20k2
Peak2 (HPLC)
20m1
Peak1 (HPLC)
10m2
Peak2 (HPLC)
20n1
Peak1 (HPLC)
20n2
Peak2 (HPLC)
20o1
Peak1 (HPLC)
20o2
Peak2 (HPLC)
20p1
Peak1 (HPLC)
20p2
Peak2 (HPLC)
20q1
Peak1 (HPLC)
20q2
Peak2 (HPLC)
20r1
Peak1 (HPLC)
20r2
Peak2 (HPLC)
20s1
Peak1 (HPLC)
20s2
Peak2 (HPLC)
20t1
Peak1 (HPLC)
20t2
Peak2 (HPLC)
20u1
Peak1 (HPLC)
20u2
Peak2 (HPLC)
20v1
Peak1 (HPLC)
20v2
Peak2 (HPLC)
20w1
Peak1 (HPLC)
20w2
Peak2 (HPLC)
20x1
Peak1 (HPLC)
20x2
Peak2 (HPLC)
20y1
Peak1 (HPLC)
20y2
Peak2 (HPLC)
20z1
Peak1 (HPLC)
20z2
Peak2 (HPLC)
20aa1
Peak1 (HPLC)
20aa2
Peak2 (HPLC)
20bb1
Peak1 (HPLC)
20bb2
Peak2 (HPLC)
20cc1
Peak1 (HPLC)
20cc2
Peak2 (HPLC)
20dd1
Peak1 (HPLC)
20dd2
Peak2 (HPLC)
20ee1
Peak1 (HPLC)
20ee2
Peak2 (HPLC)
20ff1
Peak1 (HPLC)
20ff2
Peak2 (HPLC)
20gg1
Peak1 (HPLC)
20gg2
Peak2 (HPLC)
20hh1
Peakl (HPLC)
20hh2
Peak2 (HPLC)
20ii1
Peakl (HPLC)
20ii2
Peak2 (HPLC)
20jj1
Peakl (HPLC)
20jj2
Peak2 (HPLC)
20kk1
Peakl (HPLC)
20kk2
Peak2 (HPLC)
20mm1
Peakl (HPLC)
20mm2
Peak2 (HPLC)
20nn1
Peakl (HPLC)
20nn2
Peak2 (HPLC)
20oo1
Peak1 (HPLC)
20oo2
Peak2 (HPLC)
20pp1
Peak1 (HPLC)
20pp2
Peak2 (HPLC)
20qq1
Peak1 (HPLC)
20qq2
Peak2 (HPLC)
20rr1
Peak1 (HPLC)
20rr2
Peak2 (HPLC)
20ss1
Peak1 (HPLC)
20ss2
Peak2 (HPLC)
20tt1
Peak1 (HPLC)
20tt2
Peak2 (HPLC)
20uu1
Peak1 (HPLC)
20uu2
Peak2 (HPLC)
20vv1
Peak1 (HPLC)
20vv2
Peak2 (HPLC)
20ww1
Peak1 (HPLC)
20ww2
Peak2 (HPLC)
20xx1
Peak1 (HPLC)
20xx2
Peak2 (HPLC)
20yy1
Peak1 (HPLC)
20yy2
Peak2 (HPLC)
20zz1
Peak1 (HPLC)
20zz2
Peak2 (HPLC)
20aaa1
Peak1 (HPLC)
20aaa2
Peak2 (HPLC)
20bbb1
Peak1 (HPLC)
20bbb2
Peak2 (HPLC)
20ccc1
Peakl (HPLC)
20ccc2
Peak2 (HPLC)
20ddd1
Peakl (HPLC)
20ddd2
Peak2 (HPLC)
20eee1
Peakl (HPLC)
20eee2
Peak2 (HPLC)
20fff1
Peakl (HPLC)
20fff2
Peak2 (HPLC)
20ggg1
Peakl (HPLC)
20ggg2
Peak2 (HPLC)
20hhh1
Peakl (HPLC)
20hhh2
Peak2 (HPLC)
20iii1
Peakl (HPLC)
20iii2
Peak2 (HPLC)
20jjj1
Peakl (HPLC)
20jjj2
Peak2 (HPLC)
20kkk1
Peakl (HPLC)
20kkk2
Peak2 (HPLC)
20mmm1
Peakl (HPLC)
20mmm2
Peak2 (HPLC)
20nnn1
Peakl (HPLC)
20nnn2
Peak2 (HPLC)
20ooo1
Peak1 (HPLC)
20ooo2
Peak2 (HPLC)
20ppp1
Peak1 (HPLC)
20ppp2
Peak2 (HPLC)
20qqq1
Peak1 (HPLC)
20qqq2
Peak2 (HPLC)
20rrr1
Peak1 (HPLC)
20rrr2
Peak2 (HPLC)
20sss1
Peakl (HPLC)
20sss2
Peak2 (HPLC)
20ttt1
Peakl (HPLC)
20ttt2
Peak2 (HPLC)
20uuu1
Peakl (HPLC)
20uuu2
Peak2 (HPLC)
20vvv1
Peak1 (HPLC)
20vvv2
Peak2 (HPLC)
20www1
Peak1 (HPLC)
20www2
Peak2 (HPLC)
20xxx1
Peak1 (HPLC)
20xxx2
Peak2 (HPLC)
30a1
Peak1 (HPLC)
30a2
Peak2 (HPLC)
30b1
Peak1 (HPLC)
30b2
Peak2 (HPLC)
30c1
Peak1 (HPLC)
30c2
Peak2 (HPLC)
30d1
Peak1 (HPLC)
30d2
Peak2 (HPLC)
30e1
Peak1 (HPLC)
30e2
Peak2 (HPLC)
30f1
Peak1 (HPLC)
30f2
Peak2 (HPLC)
30g1
Peak1 (HPLC)
30g2
Peak2 (HPLC)
30h1
Peak1 (HPLC)
30h2
Peak2 (HPLC)
30i1
Peak1 (HPLC)
30i2
Peak2 (HPLC)
30j1
Peak1 (HPLC)
30j2
Peak2 (HPLC)
30k1
Peak1 (HPLC)
30k2
Peak2 (HPLC)
30m1
Peak1 (HPLC)
30m2
Peak2 (HPLC)
40a1
Peak1 (HPLC)
40a2
Peak2 (HPLC)
40b1
Peak1 (HPLC)
40b2
Peak2 (HPLC)
40c1
Peak1 (HPLC)
40c2
Peak2 (HPLC)
40d1
Peak1 (HPLC)
40d2
Peak2 (HPLC)
40e1
Peak1 (HPLC)
40e2
Peak2 (HPLC)
40f1
Peak1 (HPLC)
40f2
Peak2 (HPLC)
40g1
Peak1 (HPLC)
40g2
Peak2 (HPLC)
40h1
Peak1 (HPLC)
40h2
Peak2 (HPLC)
40i1
Peak1 (HPLC)
40i2
Peak2 (HPLC)
40j1
Peak1 (HPLC)
40j2
Peak2 (HPLC)
40k1
Peak1 (HPLC)
40k2
Peak2 (HPLC)
40m1
Peak1 (HPLC)
40m2
Peak2 (HPLC)
50a1
Peak1 (HPLC)
50a2
Peak2 (HPLC)
50b1
Peak1 (HPLC)
50b2
Peak2 (HPLC)
50c1
Peak1 (HPLC)
50c2
Peak2 (HPLC)
50d1
Peak1 (HPLC)
50d2
Peak2 (HPLC)
50e1
Peak1 (HPLC)
50e2
Peak2 (HPLC)
50f1
Peak1 (HPLC)
50f2
Peak2 (HPLC)
50g1
Peak1 (HPLC)
50g2
Peak2 (HPLC)
50h1
Peak1 (HPLC)
50h2
Peak2 (HPLC)
50i1
Peak1 (HPLC)
50i2
Peak2 (HPLC)
50j1
Peak1 (HPLC)
50j2
Peak2 (HPLC)
50k1
Peak1 (HPLC)
50k2
Peak2 (HPLC)
50m1
Peak1 (HPLC)
50m2
Peak2 (HPLC)
50n1
Peak1 (HPLC)
50n2
Peak2 (HPLC)
50o1
Peak1 (HPLC)
50o2
Peak2 (HPLC)
50p1
Peak1 (HPLC)
50p2
Peak2 (HPLC)
50q1
Peak1 (HPLC)
50q2
Peak2 (HPLC)
50r1
Peak1 (HPLC)
50r2
Peak2 (HPLC)
50s1
Peak1 (HPLC)
50s2
Peak2 (HPLC)
50t1
Peak1 (HPLC)
50t2
Peak2 (HPLC)
50u1
Peak1 (HPLC)
50u2
Peak2 (HPLC)
50v1
Peak1 (HPLC)
50v2
Peak2 (HPLC)
50w1
Peak1 (HPLC)
50w2
Peak2 (HPLC)
50x1
Peak1 (HPLC)
50x2
Peak2 (HPLC)
60a1
Peak1 (HPLC)
60a2
Peak2 (HPLC)
60b1
Peak1 (HPLC)
60b2
Peak2 (HPLC)
60c1
Peak1 (HPLC)
60c2
Peak2 (HPLC)
60d1
Peak1 (HPLC)
60d2
Peak2 (HPLC)
60e1
Peak1 (HPLC)
60e2
Peak2 (HPLC)
60f1
Peak1 (HPLC)
60f2
Peak2 (HPLC)
60g1
Peak1 (HPLC)
60g2
Peak2 (HPLC)
60h1
Peak1 (HPLC)
60h2
Peak2 (HPLC)
60i1
Peakl (HPLC)
60i2
Peak2 (HPLC)
60j1
Peakl (HPLC)
60j2
Peak2 (HPLC)
60k1
Peakl (HPLC)
60k2
Peak2 (HPLC)
60m1
Peakl (HPLC)
60m2
Peak2 (HPLC)
60n1
Peakl (HPLC)
60n2
Peak2 (HPLC)
60o1
Peakl (HPLC)
60o2
Peak2 (HPLC)
60p1
Peakl (HPLC)
60p2
Peak2 (HPLC)
60q1
Peakl (HPLC)
60q2
Peak2 (HPLC)
60r1
Peak1 (HPLC)
60r2
Peak2 (HPLC)
60s1
Peak1 (HPLC)
60s2
Peak2 (HPLC)
60t1
Peak1 (HPLC)
60t2
Peak2 (HPLC)
60u1
Peak1 (HPLC)
60u2
Peak2 (HPLC)
60v1
Peak1 (HPLC)
60v2
Peak2 (HPLC)
60w1
Peak1 (HPLC)
60w2
Peak2 (HPLC)
60x1
Peak1 (HPLC)
60x2
Peak2 (HPLC)
60y1
Peak1 (HPLC)
60y2
Peak2 (HPLC)
70a1
Peak1 (HPLC)
70a2
Peak2 (HPLC)
70b1
Peak1 (HPLC)
70b2
Peak2 (HPLC)
80a1
Peak1 (HPLC)
80a2
Peak2 (HPLC)
80b1
Peak1 (HPLC)
80b2
Peak2 (HPLC)
90a1
Peak1 (HPLC)
90a2
Peak2 (HPLC)
90b1
Peak1 (HPLC)
90b2
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.
9. A method for preparation of compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the formula L compound is a compound represented by formula VII-1, and the method comprises the following steps:
in an inert solvent, reacting formula L1 compound with
to provide compound L;
wherein R is a leaving group, and the definitions of the remaining groups are as described in claim 1 .
10. A compound selected from the group consisting of:
in each formula, Rg is 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 C 6 -C 10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
the definition of each group is as described in claim 1 .
11. A pharmaceutical composition, wherein 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.
12. A method for treating hepatitis B virus infection comprising administering the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of claim 1 to a subject in need thereof.
13. 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 .
14. 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.
15. The compound of claim 1 , wherein
is a substituted or unsubstituted five or six membered ring, wherein the five or six membered ring optionally contains one or more heteroatoms selected from the group consisting of O, S, N or P; the substituted means that the hydrogen atoms on the group are substituted by one or more substituents of methyl.
16. The compound of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, cyano, difluoromethyl, difluoroethyl, monofluoromethyl, trifluoromethyl, and trifluoromethoxy.
17. A method for treating hepatitis B virus infection comprising administering the pharmaceutical composition of claim 11 to a subject in need thereof.